Category Archives: 6.9. Salvage Therapy

6.9. Salvage Therapy

– Christian Hoffmann –

Background

The term “salvage therapy” is not clearly defined in HIV medicine. As in oncology the term is currently used to refer to varying situations. Some speak of salvage only if all drug classes have failed, whereas others employ the term from second-line therapy onward. Today, many clinicians talk about salvage when there is resistance to at least two or three antiretroviral drug classes.

TCR (Triple Class Resistance) is present when viral resistance mutations against the three conventional drug classes NRTIs, NNRTIs and PIs have developed. TCF (Triple Class Failure) means that the viral load remains detectable although these three drug classes have been implemented. Analogous to MDR tuberculosis, triple class resistant viruses with additional resistance mutations are also referred to as MDR, multi-drug resistant viruses. However these terms are not uniformly defined.

Significant progress has been made for patients with TCR and/or MDR viruses over the last few years, changing therapy dramatically within a few months. For years lopinavir, T-20 and tipranavir/r were the only TCR drugs, then, within a short period in 2007/08, four new drugs were licensed. Darunavir, maraviroc, raltegravir and etravirine all have remarkable effects in the presence of multiple resistance mutations, which allow us to be optimistic and change our goals. Even with intensely pre-treated patients there is no reason not to get viral loads to below the limit of detection.

The number of patients with TCR viruses is in decline and not, as often presumed, increasing (Lohse 2005+2006, Napravnik 2007). In an analysis involving 30,000 patients from North America the proportion of patients whose second ART had virologically failed decreased from 95/100 in 1996-97 to only 13/100 person years in 2004-05 (Deeks 2008). The majority of patients with TCF originally received antiretroviral treatment with mono- and duo-therapies (Lederberger 2004). In an analysis of almost 46,000 patients in Europe the TCF rate was only 2.1%. Five and nine years, respectively, after initiation of ART the rate increased to 3.4% and 8.6% (Plato 2010). The number of patients not achieving a viral load below 50 copies/ml due to TCF remains low (Basnio 2010).

Given that this patient group is small, it is difficult to do studies with sufficient power. Homogenous populations do not really exist and every patient has his own individual therapy history and resistance pattern. In larger centers as many as 50 different combinations are used. This makes it difficult to test new salvage agents in phase II/III studies. The design of these studies is another problem: as the single use of an experimental drug within a failing regimen is ethically questionable, ART must always be optimized (OBT, optimized background therapy). If the OBT is too good, the effect of the new drug may be hidden, as many patients achieve a good viral suppression just on OBT. If the OBT is poor, the effect of the new drug may only be temporary or too weak – the window through which the efficacy of a new salvage drug can be seen is small.

The recent failure of the CCR5 antagonist vicriviroc (Gathe 2010) is only one of many examples. This shows how difficult it has become to bring a salvage agent to the market.

Preface

First a few words about daily practice: it should not be forgotten that patients with TCF, who often have a long history of being on treatment and who now find themselves once again on a precipice, need encouragement. It is important not to leave these patients without hope. It usually takes years to progress from virologic treatment failure to immunologic and finally clinical failure (see Principles of Therapy). Fortunately these patients – most having been treated for ten or fifteen years, having experienced a lot – are often not nearly as nervous as the often young HIV doctor. They have learned that there is almost always more to come.

Much is possible now in individual cases. Table 9.1 shows an example illustrating the history of antiretroviral therapy – although treatment always remained up to date, viral load of less than 100,000 copies/ml was not always achieved over the years. Finally, with the application of a new agent the patient experienced their first success after more than a decade of having a high level plasma viremia. Viral load has now been below the limit of detection for three years.

Table 9.1. Case report showing what is possible today.
Date ART

CD4 cells

Viral load

Jun 95 AZT (later, ddC, ddI)

0

N.A.

Jun 96 AZT+ddC+RTV

25

62.000

Okt 96 D4T+3TC+IDV

10

167.000

Jul 97 D4T+ddI+3TC+NVP+IDV

173

69.000

Jan 99 D4T+ddI+ABC+3TC+SQV/r

212

106.000

Sep 99 D4T+ABC+3TC+DLV+LPV/r

231

74.000

Dez 01 TDF+ddI+DLV+HU

174

84.000

Jun 03 TDF+3TC+FPV/r

143

145.000

Okt 03 TDF+3TC+ddI+TPV/r

77

733.000

Mai 04 AZT+3TC+TDF+LPV/r+T-20+DLV

43

123.000

Dez 04 AZT+3TC+TDF

32

204.000

Dez 07 AZT+3TC+TDF+DRV/r+RAL+T-20

7

>1.000.000

Jan 08

54

<50

Apr 09 AZT+3TC+TDF+DRV/r+RAL+ETV

83

<50

Mar 11

111

<50

Comment: Not all treatment modifications are shown. The switch in 2007 was deferred until DRV and RAL were available in order to use both agents simultaneously. T-20 was recycled when resistance testing did not clearly show if darunavir was still active. Although not foreseeable how long this therapy success will last, the complete suppression of the patient’s viral load is remarkable after so many years in the six figure range. A de-escalation of the current treatment (13 pills, 7 agents) seems risky at present.

Patients with TCF probably have a worse prognosis than patients without TCF (Lohse 2007). In a population-based study from the Danish HIV Cohort on all patients who experienced TCF between 1995 and 2004, the total number of genotypic resistance mutations and specific single mutations predicted mortality. In a regression model adjusted for CD4 T cell count, HIV RNA, year of TCF, age, gender and previous ART regimen, harboring at least 9 (versus less) mutations was associated with increased mortality. In contrast, other studies did not find an association between number of resistance mutations and mortality (Lucas 2004). With good CD4 T cell counts, even despite TCR viruses, the risk of developing AIDS is relatively small (Ledergerber 2004). TCR viruses have less ability to replicate and are probably less aggressive (Prado 2005). And, newer classes of drugs may be on the horizon. So, in cases of TCR or MDR, be patient. It is, however, important that patients with MDR viruses are very carefully monitored and undergo regular (monthly) full-body exams – something that is often neglected these days in the discussions on blood values and resistance testing, etc. Loss of weight, Stage B symptoms, oral candidiasis, OHL and cognitive worsening are early signs of disease progression that need to be watched for. If possible, these patients should be treated in large centers that have access to clinical studies.

Salvage with the newer drugs

A wide range of agents for the treatment of patients with limited options has been licenced in the last few years. These agents include the PIs tipranavir/r and darunavir/r (which now also has an indication for naïve patients), the NNRTI etravirine, the CCR5 anatgonist maraviroc and the integrase inhibitor raltegravir (also with an indication for naives). They have revolutionized salvage therapy and have become indispensable in the struggle against resistant viruses. Other strategies have proved less effective. The most important results on salvage therapy from large-scale studies within the last few years are shown in Table 9.2 and Table 9.3.

Table 9.2. The large randomized studies in salvage therapy.
References

Study (Agent)

Main inclusion criteria
Lalezari 2003, Lazzarin 2003, Nelson 2005

TORO 1+2
(T-20)

TCF or TCR or both, VL >5,000
Hicks 2006

RESIST 1+2
(tipranavir/r)

TCF and 1-2 primary PI-resistance, VL >1,000
Clotet 2007

POWER 1+2
(darunavir/r)

TCF and ≥ 1 primary PI-resistance, VL >1,000
Lazzarin 2007, Madruga 2007, Katlama 2009

DUET 1+2
(etravirine)

≥1 NNRTI-resistance and ≥3 primary PI-resistance, VL >5,000
Gulick 2008, Fätkenheuer 2008

MOTIVATE 1+2
(maraviroc)

TCR or TCF or both, VL >5,000 (prior treatment interruption at baseline allowed), only R5-tropic viruses
Cooper 2008,
Steigbigl 2008

BENCHMRK 1+2
(raltegravir)

TCR, VL >1,000
TCR=Triple Class Resistance, TCF=Triple Class Failure, VL=Viral load

Of note, inclusion criteria for these studies varied widely. In some studies inclusion was coupled to certain resistance mutations, others included triple class failure. There were great differences in patient populations and the definition of TCF was not consistent. The proportion of patients additionally receiving T-20 ranged from 20-44%. Different resistance scores were also used in order to determine the number of active agents in background therapy.

Accordingly, response rates vary considerably even in the placebo arms. The rates of all patients with a plasma viremia less than 50 copies/ml at 48 weeks ranged from 10% to 40%, with addition of T-20 from 11% to 62%. The response rates of patients who had received only one active agent and placebo varied from 1-24%.

Cross-trial comparisons regarding the efficacy of the new agents need to be avoided. Although this is attempted for marketing reasons: According to these trials, darunavir/r is not better than tipranavir/r. Raltegravir does not have a higher efficacy than maraviroc. The individual study matters greatly,

 

Table 9.3. The large randomized studies in salvage therapy, main results.
 

POWER

RESIST

MOTIVATE

BENCHMRK

DUET

Agent tested

DRV

TPV

MVC

RAL

ETV

Total n

245

1509

1049

701

612

Baseline characteristics

Median VL, log RNA/ml

4.5-4.6

4.7

4.9

4.5-4.7

4.8

Median CD4 T cells/µl

153-163

195-196

187-195

102-140

99-109

0-1 active drug, %*

49-55

43-45

38-44

48-51

54

Background-Therapy

With de novo T-20, %

29-33

18-23

40-44

20

25

With darunavir, %

100

0

0

25-50

100

With tipranavir, %

0

100

14-16

19-23

0

Response at 48 Wo*

In total, %

45 vs. 10

23 vs. 10

44 vs. 17

64 vs. 34

61 vs. 40

With de novo T-20, %

58 vs. 11

28 vs. 14

61 vs. 27

84 vs. 62

71 vs. 59

0-1 active drug, %

37 vs. 1

n.a.

37 vs. 6***

48 vs. 12

57 vs. 24

*Definition of an active drug varied considerably (different resistance scores were used); **Response at 48 weeks defined as viral load <50 copies/ml;  ***Data at week 24. n.a.=not applicable

What to do in patients with TCR

First of all, a resistance test should be available that was not done during a treatment interruption. Older resistance tests should also be reviewed. Resistance mutations detected earlier presumably still exist even if they are no longer detected. It is also important to check incompatibilities of the last years to spare the patient unnecessary side effects and dangerous re-exposure.

Some pilot studies report success when only new drugs are used. In the French TRIO study, 103 extensively pre-treated patients with TCF were treated with the combination RAL+ETV+MVC, out of which 86% achieved plasma viremia below 50 copies/ml at 48 weeks (Yazdanpanah 2009). In a smaller Italian study with 28 patients on the same combination RAL+ETV+MVC it reached 92% (Nozza 2010+2011).

Does it necessarily have to be new drugs? Before switching, physicians should go over the classes, one by one, depending on the individual resistance profile, even the old ones. Table 9.4 shows an overview of the major salvage strategies with regard to each class.

Table 9.4. Salvage strategies in patients with TCR to NRTIs, NNRTIs and PIs.
Drug Possible strategies, remarks
NRTIs Try to conserve mutations that reduce replication fitness, such as M184V with 3TC or FTC. Consider AZT and TDF simultaneously, due to diverging resistance pathways
NNRTIs At <3 NNRTI mutations consider etravirine (approved only with a boosted PI/r), otherwise discontinue NNRTIs
PIs Darunavir/r (good data with etravirine) or tipranavir/r
Maraviroc Tropism test? Due to non-detected dual-tropic viruses, use 2 definitively active agents such as raltegravir and T-20 (if nothing else works), remember doses adaptions when boosting with PIs
Raltegravir At least 1-2 active agents additionally needed, be aware of rapid resistance development
T-20 Consider when uncertain that at least one other agent than raltegravir and maraviroc is active

NRTIs: Even if 3TC or FTC  are no longer effective according to the resistance test, it might make sense in many cases to continue treatment with them. In this way, HIV is forced to conserve the M184V mutation, which reduces the replication fitness (Eron 2004, Campbell 2005, Castagna 2006). Due to diverging resistance pathways, another consideration may be to use AZT and TDF. This also applies when patients have already been treated with these substances. By adding AZT, viral load can be decreased under detection level in the presence of resensitising K65R (Stephan 2010).

Recycling with ddI is also possible. In the Jaguar study, 168 patients with over 1000 copies/ml and a median of 4 NRTI mutations on stable ART additionally received ddI or placebo (Molina 2005). The decrease of viral load was 0.60 logs after 4 weeks although 68% of the patients had previously received ddI. Even with these patients, the viral load decreased by 0.48 logs. However, a more recent study questions improvement of salvage regimens containing at least three new drugs by the addition of NRTIs with reduced activity according to resistance tests (Imaz 2011).

NNRTIs: In the case of NNRTIs, with less than three NNRTI resistance mutations, etravirine seems to be a good option in combination with a boosted PI (most effective with darunavir/r). In other cases it is recommended to discontinue NNRTIs. There is little doubt that once generated, resistance remains. However, with pregnant women who have received nevirapine once for transmission prophylaxis there was no elevated rate of treatment failure on nevirapine-containing regimens if ART was initiated more than 6 months after delivery – at least theoretically, it seems possible for NNRTI resistances to disappear provided one waits a longer time (Lockman 2007). However, there is no other data on recycling NNRTIs besides those for transmission prophylaxis.

PIs: In the case of PIs, the boosted PIs darunavir and tipranavir are strongly recommended, which probably have distinct resistance profiles. When resistance findings are unclear, they should be discussed with the treating physician or the virologist. If darunavir/r and tipranavir/r are not available or if they are not tolerated, one can try lopinavir/r; other PIs are probably not suitable.

Raltegravir, maraviroc, T-20: If at least one other agent is still active, it seems sufficient to treat with only one of the new agents, either maraviroc or raltegravir, to reduce the viral load to below the limit of detection. That way, one could keep the option with the other drug that could be then combined with T-20 in the future. In the case of maraviroc, a recent tropism test should be available. If maraviroc or raltegravir are the only active agents according to the resistance test, they could and should be administered together. Fortunately, there is no relevant interaction (Baroncelli 2010). If maraviroc can not be used due to tropism, one should consider T-20.

It is also important to strategize. What comes after the current regimen, and what can you do if that fails? To what extent is the patient standing with his back against the wall, immunologically? How high is the risk of progression to AIDS? The lower the CD4 T cells and the higher the viral load the more active agents are required to control the virus. If CD4 T cells are very low, it may be better to put all stakes onto one option with as many active agents as possible (at least two), instead of saving up for future options.

Such complex decisions should be discussed in a team of experienced HIV-physicians with a virologist, who can shed some light onto the resistance situation. The treating physicians should be present as well, as they are familiar with the individual situation, know the patient’s adherence history and understand what can be expected from the patient.

 

Practical tips for salvage therapy

  • First question: what is the treatment history, what level of success was there and for how long? Perform resistance testing (not during treatment interruption).
  • Choose as many new active drugs as possible when changing therapy.
  • Do not add one new drug to a failing regimen. If the clinical and immunological situation allows, wait for a second active drug.
  • Do not wait too long to switch, thus giving the virus the opportunity to develop further mutations – the higher the viral load at the time of switch, the more difficult the chances for success.
  • Do not be too demanding from the patient! Not everyone is suitable for Mega-ART.
  • Patients should be treated in larger centers where new drugs and experience are available.
  • Encourage the patient. New treatments may become available soon. A “watch and wait” approach may be possible.
  • Do not allow reversion to wild-type virus – even a failing regimen should be continued in the absence of further options.

The following strategies were used with some success pre-2007. Today, after the introduction of new drugs, they have a minor role to play.

Double PI salvage regimens

Since the introduction of darunavir/r and tipranavir/r, double PI regimens have lost their standing in salvage therapy. They will briefly be discussed because some patients are still being treated with double PI regimens.

Lopinavir/r + saquinavir/r: in vitro they have synergetic effects (Molla 2002). In the LopSaq study, 128 treatment-experienced patients were treated for different reasons (resistance, toxicity) with a nuke-free combination consisting of lopinavir/r  plus saquinavir. At week 48, 61% had reached a viral load below 400 copies/ml. However, the response in patients with numerous PI resistance mutations and low CD4 counts was poor (Staszewski 2006, von Hentig 2007).

Atazanavir/r + saquinavir/r: PK parameters for saquinavir are significantly improved by atazanavir. Response in pretreated patients was good (von Hentig 2007, Winston 2007, Manosuthi 2008). Despite the fact that saquinavir levels are elevated by atazanavir, this combination must be given with ritonavir (Haas 2003, Johnson 2005). Given the poor results in treatment-naïve patients, this combination is unlikely to play any further role  (Landman 2008).Table 9.5 gives an overview of other double PI combinations.

Conclusion: There is no longer any reason to put a patient on a double PI. Simplifying therapy should be considered for patients on a double PI regimen. One newer study showed that patients with stable viral suppression on double PI can change to darunavir/r monotherapy without risk (Cohen 2009). This would also be saving costs as darunavir, albeit the most expensive PI, is still less expensive than two older PIs together.

Table 9.5. Double PI combinations with supporting data.
Combination Daily Dose/comment Source
More favorable
Lopinavir/r + saquinavir 800/200/2000 Staszewski 2006
Atazanavir/r + saquinavir 300/200/2000 von Hentig 2007
Saquinavir/r + fosamprenavir 2000/200/1400 Boffito 2004
Lopinavir/r + indinavir 800/200/1600 Staszewski 2003
Less favorable
Lopinavir/r + fosamprenavir Poor PK data Kashuba 2005
Lopinavir/r + atazanavir Poor activity Ulbricht 2008
Lopinavir/r + nelfinavir Poor PK data, diarrhea Klein 2003
Atazanavir + indinavir Elevated bilirubin Chisolm-Burns 2007
Atazanavir + fosamprenavir Poor activity Landman 2009
Atazanavir + saquinavir without /r Poor activity Johnson 2005
Tipranavir + LPV/APV/SQV Poor PK data Walmsley 2004
Indinavir + nelfinavir Relatively poor activity Riddler 2002

Mega-ART with T-20, treatment interruptions

Intensified treatment combinations with more than three drugs – often described as mega- or giga-ART – may indeed be effective. Only well-informed and highly motivated patients can be considered for mega-ART regimens, and such approaches are often unrealistic in clinical practice. There is some evidence from the small INTENSE study that, in some cases, induction with T-20 is of benefit (Clotet 2008).

So, do structured treatment interruptions (STI) before initiation of such intensified regimens provide additional benefit? The answer is clearly no. After some encouraging results from the early GIGHAART Study (Katlama 2004) there is an overwhelming amount of data showing that STIs do not have a positive effect in heavily pretreated patients. In the CPRC064 Study in which patients interrupted treatment for four months prior to going on a salvage regimen no differences were found between patients who took an STI and those who had not (Lawrence 2003). However, it was disconcerting to see that patients who interrupted treatment not only had worse CD4 counts but also had a significantly higher frequency of severe clinical events during the follow-up period. Other randomized studies did not find any virologic benefit by interrupting treatment prior to starting an intensified salvage regimen (Ruiz 2003, Beatty 2006, Benson 2006, Walmsley 2007, Holodiny 2011). This approach is no longer an option.

Utilizing NNRTI hypersusceptibility

Viral strains are considered “hypersusceptible” to certain drugs if the IC50 (50% inhibitory concentration) for the drug is lower than that of the wild-type in phenotypic resistance tests. NNRTI hypersusceptibility was first described in January 2000 (Whitcomb 2000). It generally occurs very rarely with NRTIs but quite frequently with NNRTIs, and mostly in viruses that have developed resistance mutations against NRTIs (Albrecht 2001, Haubrich 2002). In an analysis of more than 17,000 blood samples the prevalence of hypersusceptibility in NRTI-naïve patients to efavirenz and nevirapine was 9% and 11%, respectively. In NRTI-experienced patients, it was 26% and 21% (Whitcomb 2002). Studies show that NRTI mutations, predominantly at codons 215, 208 and 118, are independently associated with NNRTI hypersusceptibility (Shulman 2004, Clark 2006).

There seems to be some evidence that patients with NNRTI hypersusceptibility have better virologic response. Of 177 highly treatment-experienced (but NNRTI-naïve) patients, 29% exhibited this type of lowered IC50 for one or several NNRTIs (Haubrich 2002). Of the 109 patients who received a new NNRTI-containing regimen, those with NNRTI hypersusceptibility achieved better results. Viral load was significantly lower even after 12 months, and the CD4 T cell count was also higher. The replicative fitness, however, does not seem to be important here (Clark 2006). Even if the real significance and molecular correlate for NNRTI hypersusceptibility remain uncertain, the consequence is clear: patients with NRTI mutations and without NNRTI resistance should receive an NNRTI if possible.

Watch-and-wait or even simplifying ART

Sometimes even the most intensified salvage regimen is not effective. Viral load cannot be suppressed to undetectable levels. What should be done in these cases? The answer is to keep going as long as the patient can tolerate the therapy. Multi-drug resistant viruses are typically slightly less aggressive than wild-type, at least for a certain period of time. A drug such as 3TC also has a positive effect on the viral load even in the presence of a confirmed M184V resistance. In a small study, in which 6 patients with MDR virus stopped only 3TC, the viral load increased by 0.6 logs (Campbell 2005). An Italian study enrolled 50 patients with a viral load of at least 1000 copies/ml on a 3TC-containing regimen, with evidence of the M184V mutation and at least 500 CD4 T cells/µl (Castagna 2006, Gianotti 2008). Patients were randomized to completely interrupt treatment or to continue with 300 mg 3TC alone because the M184V mutation reduces the replicative fitness of HIV. Patients on 3TC indeed had a significantly lower increase in viral load (0.6 versus 1.2 logs) and lost significantly less CD4 T cells (73 versus 153/µl). The M184V mutation was maintained in all patients on 3TC, and no other mutations accumulated. In contrast, a shift to wild-type was observed in all patients without 3TC. The benefit was sustained until week 144 (Castagna 2007) when 3TC was continued on a daily basis. Regarding FTC, daily doses also seems to be effective, but not when given weekly (Soria 2010).

However, ART should not be stopped completely in very immunocompromised patients who are then at risk of developing opportunistic infections. In fact, all efforts should be made in such cases to at least partially control the virus. Waiting, even on a suboptimal regimen, is a strategy that can be used to gain valuable time until new drugs are available. In such cases, ART is not being taken in vain: suboptimal ART is better than none at all, and some suppression of viral load better than none. Patients benefit even with only a slight reduction in viral load (Deeks 2000). A trial of patients with at least 2500 copies/ml on ART who were randomized to interrupt or continue ART for at least 12 weeks showed an immunological benefit for those who remained on their regimen. CD4 T cells dropped only by 15, compared to 128 cells/µl in patients on an STI (Deeks 2001). In a large cohort study, CD4 T cell counts did not drop as long as the viral load remained below 10,000 copies/ml, or at least 1.5 logs below the individual set point (Lederberger 2004).

Table 9.6. Example of a successful watch-and-wait strategy for almost three years.
Date (HA)ART

CD4 T cells

Viral load

until 1997 AZT, AZT+ddC, AZT+ddI

40 (nadir)

107,000

Mar 97 AZT+3TC+SQV-HGC

84

259,000

Oct 97 d4T+3TC+SQV+NFV

211

67,000

Jun 98 d4T+3TC+NVP+IDV/r

406

1,200

Jan 00 AZT+3TC+ABC+NVP+IDV/r

370

1,030

Mar 02 AZT+3TC+ABC+TDF+NVP+IDV/r

429

3,350

Sep 02 d4T+ddI+3TC+NVP+LPV/r

283

5,000

Nov 02*

348

7,600

Jan 03

315

16,400

Feb 03 AZT+3TC+ABC

379

6,640

May 03

241

2,400

Dec 04 AZT+3TC+ABC+TDF**

298

4,200

Jan 06

323

5,800

*Resistance testing showed a total of 20 mutations, with genotypic resistance against all drugs tested. Compliance was very good and plasma levels were always adequate. **TDF was added because of chronic HBV infection. Note: the patient’s viral load has been below the limit of detection since April 2006, when he started AZT+3TC+TDF+TPV/r+RAL.

How intensively should treatment be continued? Which drugs can be discontinued in this watch-and-wait setting? Quadruple nukes seems to be safe, as indicated by a retrospective study (Llibre 2008). NNRTIs such as nevirapine or efavirenz can be stopped if resistance mutations are found, because replicative fitness is not influenced by NNRTI mutations (Piketty 2004). Moreover, accumulation of further resistance mutations should be avoided as these may compromise newer NNRTIs such as etravirine. The same is probably true for integrase inhibitors (Wirden 2009).

What about PIs? There is data from a small pilot study showing that PI discontinuation may be safe (Deeks 2005). 18 patients, in whom the viral load remained high despite more than 6 months on ART (good compliance, appropriate efficacy), had the PIs removed from their respective ART regimens while the NRTIs were continued. Within the first two weeks, none of the patients had an increase of more than 0.5 logs, and even after 16 weeks, no increase was observed in most patients (in only 5/18 patients was there an increase of between 0.5 and 1.0 logs; in the others there was no increase, maybe even a fall). A negative immunological effect was also seen in a few patients, but this was only moderate. Repeated resistance tests showed that all PI mutations persisted in all patients in the first 12 weeks, although PIs were not being taken. One retrospective study on HIV-infected children, in which the PIs had been discontinued, was based on the same idea as the Deeks Study. Here, it was also seen that on continuous NRTI therapy, there was no increase in viral load (LeGrand 2005). Another study, however, showed that PIs maintained activity (Opravil 2009).

Results from one of our own patients where this approach has been successful for almost three years are shown in Table 9.6. Resistance testing after two years showed that there were no changes in the MDR virus. Watch-and-wait on a simple NRTI regimen seems feasible in some patients for a limited period of time. The reasons for this phenomenon, however, are still not understood but it is possible that multiresistant viruses cannot easily mutate back. With PI therapy alone, this does not appear to be effective – in 5/5 patients, in whom only the nucleoside analog was stopped, viral load increased significantly (Deeks 2005). As total patient numbers are still very small in the data presented to date, many observers remain skeptical. The main question is how long and in which patients these strategies might be successful. It is thus advisable to monitor CD4 T cells at short intervals.

References

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Albrecht MA, Bosch RJ, Hammer SM, et al. Nelfinavir, efavirenz, or both after the failure of nucleoside treatment of HIV infection. N Engl J Med 2001, 345:398-407.

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Baroncelli S, Villani P, Weimer LE, et al. Raltegravir plasma concentrations in treatment-experienced patients receiving salvage regimens based on raltegravir with and without maraviroc coadministration. Ann Pharmacother 2010, 44:838-43.

Beatty G, Hunt P, Smith A, et al. A randomized pilot study comparing combination therapy plus enfuvirtide versus a treatment interruption followed by combination therapy plus enfuvirtide. Antivir Ther 2006; 11:315-9.

Benson CA, Vaida F, Havlir DV, et al. A randomized trial of treatment interruption before optimized antiretroviral therapy for persons with drug-resistant HIV: 48-week virologic results of ACTG A5086. J Infect Dis 2006; 194: 1309-18.

Boffito M, Dickinson L, Hill A, et al. Steady-state pharmacokinetics of saquinavir hard-gel/ritonavir/fosamprenavir in HIV-1-infected patients. J AIDS 2004, 37:1376-1384.

Campbell TB, Shulman NS, Johnson SC, et al. Antiviral activity of lamivudine in salvage therapy for multidrug-resistant HIV-1 infection. Clin Infect Dis 2005, 41:236-42.

Castagna A, Danise A, Galli L, et al. 144-week clinical and immunological outcome of HIV-1-infected subjects receiving lamivudine monotherapy or treatment interruption. Abstract 516, 14th CROI 2007, Los AngelesA.

Castagna A, Danise A, Menzo S, et al. Lamivudine monotherapy in HIV-1-infected patients harbouring a lamivudine-resistant virus: a randomized pilot study (E-184V study). AIDS 2006;20:795-803.

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Filed under 6. ART 2011, 6.9. Salvage Therapy, Part 2 - Antiretroviral Therapy

6.10. When to Stop ART

A review of treatment interruption

– Christian Hoffmann –

Many treatment interruptions occur without the clinician’s knowledge. In the CASCADE cohort (8300 patients from Europe) the probability of treatment interruptions for at least several weeks was 16% (Touloumi 2006). Treatment interruptions are an important part of antiretroviral therapies whether as a clinician one approves of them or not. The following chapter provides an overview of the current knowledge in this area.

Viral load and CD4 T cells during treatment interruptions

Almost all patients who stop treatment experience a rebound in viral load within a few weeks, even patients in whom this has been undetectable for several years.  Viral load is usually detectable again within 10-20 days (Chun 1999, Davey 1999, Harrigan 1999). The viral load in compartments such as the CNS, as well as in semen and vaginal fluids, parallels that in the plasma (Garcia 1999) and is detectable in semen within only a few weeks (Ananworanich 2011). Patients should therefore be informed about the higher risk of transmitting HIV (Burman 2008). Some cases report infections during interruption (Bernasconi 2001). There may be an increased risk of maternofetal transmission, even if ART is interrupted in the first trimester (Galli 2009).

Frequently, an initial overshooting rebound is observed (De Jong 1997), and only after a few weeks does the viral load settle to its original, pre-treatment level (Hatano 2000). The rebounding virus evidently does not originate from latent reservoirs; other cell populations must exist from which this new virus is produced so quickly (Chun 2000, Ho 2000, Imamichi 2001).

Treatment interruptions can have serious immunological consequences. Often, CD4 T cell counts drop within a short time to pre-treatment levels. The ground that has been gained on ART is rapidly lost. The drop is bi-phasic, and the drop more pronounced in the first few months (Fagard 2005, Wit 2005, Skiest 2006). CD4 T cell losses vary greatly between patients but may reach 200 or 300/µl within a few weeks. The higher and faster the CD4 T cells increase on ART, the more rapid their decline (Tebas 2002). The CD4 nadir is also important. The lower it was and the older the patient, the more rapidly the count drops again (Maggiolo 2004, Molina 2006, Skiest 2006, Touloumi 2006). Probably there is also an association with high proviral DNA level at treatment interruption (Piketty 2010).

The loss of CD4 T cells during an interruption may not be regained as quickly. In a prospective study, we saw a significant disadvantage for patients undergoing treatment interruptions. After a follow up of 18 months, CD4 T cells were more than 120/µl less in these patients than in matched patients who had not interrupted treatment (Wolf 2005). This was also observed in the SMART study.

The risks: resistance, clinical problems, AIDS

Viral resistance always has to be anticipated whenever there is viral replication in the presence of suboptimal drug levels, and thereby resistant mutants gain a selective advantage over the wild-type virus. As a result, there are concerns that resistance could develop both during the washout phase of medication (increasing viral replication with insufficient plasma levels) and on re-initiation of treatment (continued replication despite sufficient plasma levels).

However, in the case of single treatment interruptions, the probability of this does not appear to be particularly high, as shown in 1999 by the small French COMET Study, one of the first studies on treatment interruption (Neumann 1999). But there is no certainty as to whether interruptions might not eventually lead to development of resistant isolates, which merely require more time until they are able to dominate. Mathematical models show that this risk – at least theoretically – is not low, especially if viral load rises to high levels (Dorman 2000, Bonhoeffer 2000).

The risk of resistance is probably higher for repeated treatment interruptions. In several studies, these have led particularly to NNRTI- or 3TC-resistance (Martinez-Picado 2002, Schweighardt 2002, Ruiz 2007). The risk seems particularly high for strategies involving stopping and starting at fixed intervals (see below). Table 10.1 describes the example of a patient who was clinically well and who interrupted treatment. It was probably the repeated stopping and starting of ART that ultimately led to resistance in this case.

Table 10.1. Example of the development of resistance due to repeated ART interruptions*.
Date ART/comments

CD4 T cells

Viral load

Jun 97 AZT+3TC+SQV

288

67,000

Oct 99 ART stopped, patient feeling well

540

<50

Dec 99 Diagnosis of autoimmune hyperthyroidism

400

63,000

Jan 00 AZT+3TC+NVP (+ carbimazole)

260

74,000

Feb 00 Diagnosis of anemia (Hb 7.3 g/dl)ART stopped again

347

1500

Mar 00 d4T+3TC+NVP (+ carbimazole)
Apr 00 Resistance mutations K103N, M184V

360

2400

*During the first treatment interruption the patient developed autoimmune hyperthyroidism, the treatment of which led to anemia after re-initiation of ART, so ART was interrupted again. As a result, resistance developed against NNRTIs and 3TC. Autoimmune phenomena in the context of treatment interruption as seen in this patient have not previously been described.

The sharp increase in viral load that may often occur can present as a retroviral syndrome. The symptoms are similar to acute HIV infection, with lymphadenopathy, fever, asthenia and malaise (Colven 2000, Zeller 2001). Thrombocytopenia occurs in 25% of cases, especially when low thrombocytes existed previously (Ananworanich 2003, Bouldouyre 2009). The blood count needs to be monitored, especially in patients with a history of thrombocytopenia.

Finally, attention should be paid to patients who are coinfected with hepatitis B. If the HBV treatment with 3TC, FTC or tenofovir is interrupted, HBV rebound can result in fulminant and life-threatening hepatitis (Sellier 2004, Dore 2010). It is therefore advisable to monitor these patients very carefully and read the liver enzymes at least every two weeks.

The risk of AIDS seems to be low for single interruptions provided the immune defect is only moderate. In the Swiss Cohort, the risk of progression was not increased (Taffe 2002). In 133 patients who interrupted treatment we observed no increased risk of AIDS after 24 months compared to 262 matched controls (Wolf 2005). However, almost all patients in this study were immunologically stable throughout. The risk is probably higher in patients with severe immunodeficiency (Deeks 2001, Lawrence 2003). The CPRC064 Study in which 270 patients with MDR virus and clear immunodeficiency (median 144 CD4 T cells/µl) were randomized before a salvage regimen either to a four-month treatment interruption or not was stopped because of high risk of progression. In comparison with the control group, a significantly higher progression to AIDS (17 versus 5) occurred in the group interrupting therapy. In a multivariate analysis, two factors were predictive for death or progression: treatment interruption and the CD4 T cell count at the time of interruption. The risk increased by 1.4 with every drop of 50 CD4 T cells. This study demonstrates that severely immunocompromised patients are particularly at risk of developing AIDS during treatment interruptions of several months. Treatment interruptions should be avoided in such patients. Newer data from the SMART Study, however, show that even with higher CD4 T cells treatment interruptions can lead to the development of AIDS (see below).

STI for immunologic reasons: no effects

Hardly any patient has become as famous as the acutely-infected man treated in a Berlin practice a few years ago who, with a viral load of approximately 80,000 copies/ml, began an ART regimen consisting of ddI, indinavir and hydroxyurea. The virus rapidly became undetectable. After several problems – and two short treatment interruptions – ART was completely stopped after 176 days. Surprisingly, even without drugs plasma viremia has remained below the level of detection for more than five years. Although virus was still detectable in lymph nodes, thus excluding eradication, the immune system in this case – referred to as the Berlin Patient (Lisziewicz 1999) – was obviously capable of durable control of infection. Why? Was it the early initiation of therapy, the hydroxyurea, or the treatment interruptions? No one knows the answer, even today. There may be a completely different explanation: it is possible that certain host factors in this patients that have not yet been elucidated could have influenced the course of disease – completely independently of ART, STI or hydroxyurea (Bloch 2006).

STIs have been extensively investigated in acutely-infected patients (see chapter on Acute HIV infection). The theory of “endogenous vaccination” seems plausible. Transient increases in viral load could strengthen HIV-specific immune responses, which decline with increasing viral suppression on ART.

In several pilot studies from 2000/2001 successive interruptions seemed to indeed prolong the time to viral rebound or decrease the rate of rebound and, in parallel, there were measurable improvements in HIV-specific CD4 or CD8 T cell immune responses (Haslett 2000, Garcia 2001, Lori 2000, Ortiz 1999, Papasavvas 2000, Ruiz 2000). However, almost none of these studies included more than 2-6 patients, and a control group was usually missing.

STIs were finally put to the test in the Spanish-Swiss SSITT Study (Oxenius 2002, Fagard 2003): 133 patients were monitored throughout four ten-week treatment cycles, each consisting of eight weeks ART and two weeks of treatment interruption. After this, ART was permanently interrupted. Treatment success – defined as a viral load below 5000 copies/ml without ART after 52 weeks – occurred in 21/99 patients. However, 5/21 patients had a low viral load even before the initiation of ART. Most importantly, none of the 32 patients with a pre-ART viral load above 60,000 copies/ml achieved a viral load of less than 5000 copies/ml. The viral load set point was lowered in only a few patients, usually those with low initial viral load, despite repeated STIs. In contrast to acute infection, improvement of HIV-specific immune response seems unlikely in the setting of chronic HIV infection. SSITT clearly showed that treatment interruptions on immunological grounds alone are not justified and are dangerous.

Approaches with immunomodulatory drugs such as hydroxyurea (Foli 2004), mycophenolate (Garcia 2004), steroids (Ulmer 2005) or IL-2 (Henry 2006, Kilby 2006, Angus 2008) took place to lengthen the period of STIs. These approaches, whose benefits anyway seemed questionable to this author, are still in the experimental phases and not justified outside studies. The same holds true for vaccination strategies (Harrer 2005, Jacobson 2006, Goujard 2007, Harrer 2008).

STI as a salvage strategy for MDR virus: no effects

In most patients with MDR virus, treatment interruption leads to a gradual shift back to wild-type and a loss of resistance. Resistance testing during treatment interruption is often of little use since mutations disappear from the blood as early as two weeks after treatment interruption (Devereux 1999). In modestly immunosuppressed patients, this shift is observed more frequently and faster. In more advanced stages of disease and with a longer duration of treatment, it lasts longer (Miller 2000, Izopet 2000), and sometimes after a longer interruption of therapy, no shift can be seen (Halfon 2005). When the shift is visible, PI mutations are the first to disappear, while NNRTI mutations are more protracted because they hardly affect viral fitness (Deeks 2001, Birk 2001). It is assumed that the wild-type merely dominates the resistant mutants. Special PCR methods can detect low quantities of resistant virus during STI (Izopet 2000) and when treatment is restarted resistance mutations rapidly re-dominate (Delaugerre 2001). Only a few cases have been described in which resistance mutations were apparently flushed out completely. There is one patient (Walter 2002) who was not able to attain sufficient viral suppression despite intensified ART, and who then interrupted treatment. During the following seven months of treatment interruption there was a gradual reversion to wild-type, and after re-starting ART (which, according to previous resistance testing, should have had no effect) the viral load was successfully suppressed for several years.

Can patients with MDR improve the effect of the salvage regimen if they have had a previous interruption of treatment? At least two studies have shown that the shift resulting from treatment interruptions can be beneficial for salvage strategies (Miller 2000, Katlama 2004). However, this data is in contrast to that of numerous other studies in which an increased risk of AIDS was occasionally seen during treatment interruptions (Lawrence 2003, Lawrence 2006, Ruiz 2003, Ghosn 2005, Beatty 2006, Benson 2006, Walmsley 2007, Holodny 2011). In view of the risk of AIDS and the lack of evidence regarding the benefits treatment interruptions are no longer justified.

STI for reduction of toxicity

Every antiretroviral therapy can cause side effects. Is it possible to reduce toxicity by treatment interruptions? Increased transaminases or lipid levels can drop quite rapidly after stopping treatment (Hatano 2000, Wolf 2005). However, it is not clear, whether this is relevant in reducing the risk of cardiovascular disease. In SMART (see below), the risk of cardiovascular and metabolic complications during STIs was actually higher. In contrast to other studies, no relevant improvement of lipids was observed (Lampe 2010). At present, it seems at least questionable that, through solitary or repeated interruptions, the cardiovascular risk profile can be improved.

What about lipodystrophy and mitochondrial toxicity? At least two studies have shown that, after a few months, mitochondrial DNA can regenerate itself following a treatment break (Cote 2002, Mussini 2005, Kim 2007). In contrast, another study showed no effect (Negredo 2006). Whether or not a clinically manifest lipodystrophy improves, remains to be seen. At least short treatment interruptions have not had any effect on morphological changes (Hatano 2000). A six-month ART interruption markedly improved adipose tissue function, although fat distribution did not visibly change (Kim 2007). Substudies from the SMART trial (see below), so far the largest, showed a moderate positive effect on peripheral fat, lipids and bone mineral density during CD4-guided treatment interruptions (Martinez 2010). Another subtrial showed more reduction of bone density on continued therapy than during interruption – however, numbers of a slightly reduced fracture risk during interruptions are still small (Grand 2009).

Conclusion: Although a treatment interruption is theoretically the solution to long-term toxicity on ART a convincing argument has not been provided by the data so far. Nevertheless, we will try to outline some relevant data. It is essential to distinguish between structured intermittent treatment with fixed intervals and interruptions that are individualized based on CD4 T cell count, in which case the interruption period depends on the patient’s immunological situation.

Structured Intermittent Treatment (SIT, Fixed Intervals): In the initial phase immediately following ART interruption the viral load usually remains low. Plasma viremia only reaches pre-treatment levels after about four, sometimes six weeks. The risk of developing resistance is presumably small at lower levels of viral replication (Bonhoeffer 2000). Does this indicate that ultra-short treatment interruptions could be utilized to reduce drug use, costs and long-term toxicity? In two NIH pilot studies on SIT in chronically infected patients ART was administered as seven days of treatment and seven days interruption (7-on-7-off). At 44-84 weeks, neither the viral load nor the proviral DNA increased (Dybul 2001+2004). CD4 T cells and HIV-specific immune responses remained unchanged suggesting that the immune system is probably unaffected by such ultra-short breaks in treatment. A significant reduction in lipid levels did, however, occur. Some patients experienced several blips (temporary increases in viral load) to above 100 copies/ml. It is impossible to predict whether this treatment strategy might result in a higher risk of resistance in the long term. There are still no larger studies, and it has become suspiciously quiet in this area. In addition, patients in the NIH studies were carefully selected, with good immune status and many years of viral suppression. This strategy is probably only applicable to a select group of patients. A three-armed study from Thailand showed a negative experience with the 7-on-7-off approach (Cardiello 2005). In this study, 19/36 patients experienced virologic treatment failure within a short period of time, and this treatment arm was consequently stopped prematurely. The main reason for this appears to lie in the fact that the majority of patients were NRTI-experienced. This means that if NRTIs are unstable, such on-off strategies are problematic.

ART only on weekdays? This approach was taken by the randomized FOTO Study (Five On, Two Off) in which TDF+FTC plus efavirenz was either given daily or from Monday to Friday and stopped at the weekends (i.e., sparing 28%). 60 patients were enrolled who showed an undetectable viral load for at least three months prior to the study. After 48 weeks, viral load increased in one patient despite low trough levels (Cohen 2007+2009).

In contrast, longer interruptions, over several weeks, with fixed intermittent treatment seem to be unfavorable. Results from a randomized NIH study with fixed intervals (each with one month of STI, two months of treatment) were disconcerting (Dybul 2003). The SIT arm contained significantly more patients with virologic treatment failure. Resistance mutations developed particularly against NNRTIs and 3TC, so that the study was stopped early. In the SSITT Study (2 weeks STI, 2 months ART) some resistance was seen (Yerli 2003), likewise in an Italian study (Palmisano 2007), but not in the French WINDOW Study (two months each of STI and therapy) (Marchou 2006). In the DART trial, the risk of AIDS was increased during the three months of treatment interruption (DART 2008).

CD4 T cell driven interruptions: Beside fixed intervals, whether short or long, there is another approach whereby interruptions are individualized based on CD4 T cell count. In other words, in patients with a good CD4 count, ART is interrupted until the CD4 count drops below some immunological cut-off and only then is it resumed. Over the last few years, many non-randomized studies with differing cut-off points and very heterogeneous patient populations came to the conclusion that this approach is safe and allows for a considerable reduction in drug exposure (Maggiolo 2004, Skiest 2004, Fernandez 2005, Mussini 2005). In the meantime, a few randomized studies compare such CD4-driven intervals with continuous administration of ART. The relevant data and results of these studies are given in Table 10.2.

It is clear that the results of these randomized studies differ considerably. While TIBET, Staccato or ACTG 5170 produced the verdict that CD4 T cell-driven interruptions are safe, two other studies, Trivacan and SMART came to other conclusions.

Table 10.2. Randomized studies of CD4 T cell guided structured treatment interruptions.
Source

n

CD4 BL

CD4 Restart

Clinical findings in the STI arms
TIBET, Ruiz 2005

201

>500
>6 Mo

<350
or VL >100,000

Some retroviral syndromes, some de novo NNRTI resistance, otherwise clinically safe (not a single AIDS case)
SMART, El Sadr 2006

5472

>350

<250

Morbidity and mortality risk low, but significantly raised. See Table 10.3.
Trivacan, Danel 2006

326

>350

<250

Morbidity significantly raised (double) due to invasive bacterial infections.
Staccato, Ananworanich 2006

430

>350

<350

Clinically safe (slightly more side effects in ART arm; more candidiasis in STI arm). No evidence of resistance.
ACTG 5170, Skiest 2006

167

>350

<250

In general safe, with risks only elevated when CD4 nadir was low.
LOTT, Maggiolo 2009

329

>700

<350

Clinically safe. More pneumonias but less cardiovascular events, no evidence of resistance.
FU=follow up; Mo=months; BL=baseline

In particular, the results of the SMART Study, which started in 2002, caused a sensation. In this, the largest randomized HIV study of all time, the cut-off levels for stopping ART were 350 cells/µl, and 250 cells/µl for re-initiating it. In the end, 318 centers in 53 countries recruited a total of 5472 patients. In 2006 an independent data safety monitoring board concluded that therapeutic interruptions result in an increased risk of AIDS – in the interruption arm, approximately twice as many AIDS illnesses were observed at follow-up, over an average of 18 months. This included severe opportunistic infections as well as malignant tumors. In fact, the overall risk was low, but so significantly elevated that the unusual and far-reaching decision was made to end the study.

In addition it was observed that cardiovascular incidents in the interruption arm did not become less frequent, but actually increased. The clinical incidents in SMART (http:/www.smart-trial.org/news.htm) are shown in the following table.

Table 10.3. Different events occurring in SMART, per 100 patient years (El Sadr 2006).
 

STI (n)

Control (n)

Odds ratio

Progression of disease or death

3.7 (120)

1.3 (47)

2.6 (1.9-3.7)*

Death

1.5 (55)

0.8 (30)

1.8 (1.2-2.9) *

Cardiovascular/renal/hepatic events

1.8 (65)

1.1 (39)

1.7 (1.1-2.5)*

Grade IV toxicity

5.0 (173)

4.2 (148)

1.2 (1.0-1.5)*

*Significant difference. **95% Confidence interval.

Quality of life did not improve in therapy interruptions – it even declined (Burman 2008). More recent studies showed that clinical and immunological disadvantages remained, even when ART was resumed (El Sadr 2008).

However, even after SMART, not all questions were answered. A striking fact was the high incidence of clinical occurrences compared to Staccato, a study involving 430 patients. As measured by the AIDS/mortality rates of ART, there should have been at least 17 cases in Staccato – instead there was not one. Moreover the significantly higher risk of an AIDS-defining malignancy during therapy interruption (Silverberg 2007) was questionable as the majority of the patients who developed KS or lymphoma in SMART had already suffered from AIDS illnesses before. Why were these patients enrolled in the SMART study?

Most of the deaths in the interruption group were not ascribed to AIDS (only 4 compared to 3 cases in the control group) but to cancer which is normally not associated with HIV infection (11 versus 5), and to cardiovascular incidents (7 versus 4). Cases of death of unknown cause were also more frequent in the interruption group (15 versus 3). One can only speculate about the increased cardiovascular, renal and hepatic incidents in the interruption group. How many patients interrupted therapy that should not have? How many patients with chronic hepatitis B experienced a HBV rebound during interruption, how many patients with previous HIVAN developed renal problems, how many patients decided to stop concomitant medications (statins) that led to a cardiovascular event? However, there are some newer studies that show an increase of inflammatory or coagulation parameters during therapy interruption (Kuller 2008, Calmy 2009). Cystatin C, a measure for renal function, also increases (Mocroft 2009).

Despite all these questions, the conclusion remains that it is difficult to find a reasonable argument for treatment interruption. Especially the argument that therapy interruptions improve quality of life is no longer acceptable. One can discuss higher values for initiation and interruptions, but there will certainly not be any second SMART with new starting/stopping values for some time.

Patients should always be encouraged to continue ART. Thanks to the new classes, the options have widened, enabling us to react to many side effects. If the patient, after discussion, still wishes to interrupt therapy the wish should be respected. The interruption will happen anyway with or without the doctor’s agreement. A monitored interruption is better than one done secretly behind the physician’s back. Under strict surveillance the risk for complications is rather low.

Practical tips for treatment interruptions

  • If there are no problems with ART, there is no reason to stop it.
  • To reverse resistance or for immunologic reasons, i.e., from a strategic point of view, STIs are not useful.
  • A positive effect on cardiovascular incidents or lipodystrophy has not been confirmed. From the SMART Study, this seems highly unlikely.
  • The patient’s wish for a break should be respected. The interruption will happen whether the clinician agrees or not. A supervised treatment interruption is always better than one undertaken without the awareness of the clinician.
  • Beforehand, information should be provided on possible clinical (retroviral syndrome, AIDS), immunologic (loss of CD4 T cells) and virologic (resistance) consequences.
  • Patients must be aware that the risk of infection increases – even after a longer suppression, viral load returns to initial levels after 4-6 weeks without ART.
  • Beware of HBV coinfection (danger of hepatitis flare-ups)
  • CD4 T cells (including percentage), viral load, and blood count (i.e., thrombocytes) should be monitored monthly during interruptions.
  • Risk of resistance is possibly higher with NNRTIs (choose robust regimens and stop NNRTIs several days earlier if possible – consider the half-life of the drugs).
  • Patients who started ART “too early” according to current standards can probably interrupt safely.
  • Resistance testing during treatment interruptions is not useful – it usually only measures the wild-type.
  • Start with ART again, but not too late.

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Haslett PA, Nixon DF, Shen Z, et al. Strong HIV-specific CD4+ T cell responses in a cohort of chronically infected patients are associated with interruptions in anti-HIV chemotherapy. J Infect Dis 2000, 181: 1264-72.

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Filed under 6.10. When to Stop ART?, 6.9. Salvage Therapy, Part 2 - Antiretroviral Therapy

6.11. Monitoring

– Christian Hoffmann, Christian Noah –

Which parameters should be included in routine laboratory monitoring of HIV-positive patients? What results can be expected? This section deals with viral load, CD4 T cells, routine checks, and plasma levels. Resistance and tropism tests are the subject of a separate chapter (see HIV Resistance Testing). For the tests to be performed on initial presentation see The New Patient.

Viral Load

Viral load is the amount of HIV RNA in the blood. Alongside the CD4 T cell count, viral load has become the most important surrogate marker for HIV infection (Hughes 1997, Mellors 1997, Lyles 2000, Ghani 2001, Phillips 2004). It provides information on how high the risk is for disease progression and whether antiretroviral therapy is indicated; it is the critical value in determining the success of therapy. Viral load assays measure the amount of HIV RNA (viral genetic material), which correlates directly with the number of virions. The units are viral copies/ml (or genome equivalents). This is reported either as a direct whole number or as a logarithmic number. A change of one or more logs refers to the change in viral load by one or more decimal powers. Many labs provide both values, the number and the log. There is no standardized international unit/ml as in used in hepatitis B or C.

Number of copies Log10
10 1.0
50 1.7
100 2.0
500 2.7
1000 3.0
10,000 4.0
50,000 4.7
100,000 5.0
1,000,000 6.0

Assessment

The higher the viral load, the higher the risk of decrease in CD4 T cells, with subsequent disease progression or occurrence of AIDS-related illnesses (Mellors 1997, Lyles 2000, Phillips 2004). A viral load above 100,000 copies/ml (sometimes even above 50,000 copies/ml) is considered to be high; a value below 10,000 copies/ml (sometimes below 5000 copies/ml), low. However, these thresholds are not absolute and only provide points of reference.

The effects of plasma viremia on immune status can vary greatly between individuals. There are some patients whose CD4 T cells remain stable for relatively long periods despite having a high viral load, while others experience a rapid drop, although the viral load is relatively low. Even in the so-called elite controllers in which the viral load is undetectable without ART a slow but constant drop in the CD4 cells can be observed (Stellbrink 2008).

Viral load is probably lower in women than in men. In a meta-analysis, the difference was 41% or 0.23 logs (95% CI 0.16-0.31 logs) (Napravnik 2002). The reason for this phenomenon remains unclear and whether it should have an impact on the indication for treatment is still the subject of debate.

Methods

Three methods or assays are currently used to measure viral load: Reverse Transcription-Polymerase Chain Reaction (RT-PCR); branched-chain DNA (bDNA); and, occasionally, Nucleic Acid Sequence-Based Amplification (NASBA). These three methods differ both in levels of detection and in the linear range within which measurement is reliable or reproducible (see Table 11.1). In the case of PCR and NASBA, the viral RNA is transformed in several enzymatic steps and then amplified to measurable amounts. Detection occurs after binding of marked DNA fragments. bDNA does not require an enzymatic step; signal amplification occurs via binding of branched DNA fragments to viral RNA.

The market for assay systems is very dynamic. New assay systems will become available, existing ones further developed. Siemens, for example, offers an RT-PCR in addition to bDNA technology. Roche concentrates on RT-PCR and is working on additional functions such as “dual-target detection” for more successful results. This means that not one section of the viral RNA, like before, but two sections can be duplicated at the same time. If duplication fails in one section on account of the high variability of the HIV genome (the result in this case would be incorrect negative), it will be duplicated in the second section. Besides already established manufacturers, newer companies such as Qiagen are trying to gain market share. Experience will show whether their testing systems are reliable or not.

Recent further developments also concern a reduction below detection level which is at 20 copies/ml in the most sensitive tests. Clinical relevance of a viral load below 50 copies/ml is questionable due to lack of data. It should be noted that a higher sensitivity can lead to insecurity in patients and clinicians and to more frequent control tests.

Although intra-assay variability is fairly good for all three methods, methodological variations should be carefully considered. Differences of less than 0.5 logs are not considered significant. A decrease from 4.3 to 3.9 logs, for example (corresponding to a decrease from approximately 20,000 to 8,000 viral copies/ml) does not necessarily signify a drop in viral load. The same holds for increases in viral load. Changes of up to threefold can therefore be irrelevant. Patients should be made aware of this.

Considerable differences exist between the methods (Coste 1996) and to change from one method to another is therefore generally not advisable. The results obtained by bDNA are usually lower than the PCR by a factor of 2. Different subtypes are also detected with varying success according to the method employed (Parekh 1999). One should be particularly cautious in patients from Africa and Asia with non-B subtypes in whom the viral load at first presentation can be unexpectedly low. In such cases, use of a different assay may actually be indicated. However, newer versions with improved primers are probably superior in measuring even unusual HIV subtypes with adequate sensitivity.

All assays have a linear dynamic range, outside of which precise numbers are not so reliable. The following rule applies: use one method, one laboratory. The laboratory should be experienced and routinely perform a sufficiently large number of tests. Measurement should take place as soon as possible after blood withdrawal, and correct collection and shipping of centrifuged plasma is also important (contact the laboratory ahead of time on these issues).

Tabelle 11.1. Methods of measurement.
Company

Test

Technology

Detection limit (co-pies/ml)

Linear Range (copies/ml)

Roche Diagnostics

COBAS TaqMan HIV-1 Test; v2.0

RT-PCR

20

20–10,000,000

Siemens Healthcare Diagnostics

Versant HIV-1 RNA 1.0 Assay (kPCR)

RT-PCR

37

37–11,000,000

Abbott Molecular

Abbott RealTime HIV-1

RT-PCR

40

40–10,000,000

Siemens Healthcare Diagnostics

Versant HIV-1 RNA 3.0 Assay (bDNA)

bDNA

65

50–500,000

Biomérieux

NucliSENS EasyQ HIV v. 2.0

NASBA

250

25–7,900,000

Influencing factors

Apart from methodological variability a host of other factors may influence levels of viral load including vaccinations and concurrent infections. During active OIs viral load is often high. One study showed a 5- to 160-fold elevated viral load during active tuberculosis (Goletti 1996). Viral load can also increase significantly during syphilis and declines after successful treatment (Buchacz 2004, Kofoed 2006, Palacios 2007). In a large retrospective study, 26% of transient viremia in patients on ART were caused by intercurrent infections (Easterbrook 2002). In these situations, determining the viral load does not make much sense.

Following immunizations, for instance for influenza (O’Brien 1995) or pneumococcus (Farber 1996), the viral load may be transiently elevated (Kolber 2002). As the peak occurs one to three weeks after immunization, routine measurements of viral load should be avoided within four weeks of immunization. It should be noted that not every increase is indicative of virologic treatment failure and resistance. Slight transient increases in viral load, or blips, are usually of no consequence, as numerous studies in the last few years have shown (see chapter on Goals and Principles of Therapy). The possibility of mixing up samples always has to be considered. Unusually implausible results should be double-checked with the laboratory, and if no cause is found there, they need to be monitored – people make mistakes. Should there be any doubt on an individual result; the lab should be asked to repeat the measurement from the same blood sample.

Viral kinetics on ART

The introduction of viral load measurement in 1996-1997 fundamentally changed HIV therapy. The breakthrough studies by David Ho and his group showed that HIV infection has significant in vivo dynamics (Ho 1995, Perelson 1996). The changes in viral load on antiretroviral therapy clearly reflect the dynamics of the process of viral production and elimination. The concentration of HIV-1 in plasma is usually reduced by 99% as early as two weeks after the initiation of ART (Perelson 1997). In one large cohort, the viral load in 84% of patients was already below 1000 copies/ml after four weeks. The decrease in viral load follows biphasic kinetics. In the first phase, i.e., within the first three to six weeks, an extremely rapid drop occurs, followed by a longer phase during which the viral load gradually decreases further (Wu 1999).

The higher the viral load at initiation of therapy, the longer it takes to drop below the level of detection. In one study, the range was between 15 days with a baseline viral load of 1000 and 113 days with a baseline of 1 million viral copies/ml (Rizzardi 2000). The following figure shows a typical biphasic decrease in viral load after initial high levels.

Numerous studies have focused on whether durable treatment success can be predicted early (Thiabaut 2000, Demeter 2001, Kitchen 2001, Lepri 2001). In a study on 124 patients, a decrease of less than 0.72 logs after one week was predictive of virologic treatment failure in more than 99% of patients (Polis 2001). According to another prospective study, it is possible to predict virologic response at 48 weeks even after 7 days (Haubrich 2007). However, this has little clinical relevance, and in our opinion it is pointless to start measurement of viral load only one or two weeks after initiation of therapy.

 

Figure 1: Typical biphasic decrease in viral load on ART. Viral load was initially very high, and reached a level below 50 copies/ml only at week 32. Note the temporary increase at week 24, which is possibly due to methodological variability. ART was not changed.

We recommend to measure viral load every four weeks until it has dropped to below detection of 20-50 copies/ml. Once that is achieved, measurement every three to four months is enough. Eventually, longer intervals are possible (Chaiwarith 2010). In case of rebound, closer monitoring becomes necessary. Within the first 4 weeks of therapy initiation the viral load should be reduced by a factor of 100, after 3-4 months (6 months if viral load was high) it should be below the level of detection.

Viral load can also be measured fairly reliably in body fluids other than blood or plasma (for example cerebrospinal, vaginal or seminal fluid). However, such tests are usually performed for scientific purposes and are not officially licensed for other reasons.

Practical tips for dealing with viral load (see chapter Goals and Principles of Therapy)

  • Use only one assay, if possible.
  • Use only one experienced laboratory, if possible, no home-brewed assays.
  • Watch for assay variability (up to half a log) and explain this to the patient.
  • Monitor viral load every four weeks with new ART until the viral load is below the level of detection (50 copies/ml).
  • Then measure viral load sparingly – on successful ART every three months may be sufficient.
  • Not on ART, measurement every three months is usually sufficient.
  • Do not measure shortly after vaccinations or with concurrent infections.
  • Implausible results should be rechecked after 2-4 weeks.
  • Consider differences between subtypes (in some cases it may be useful to use another method).

CD4 T cells

CD4 T cells are T lymphocytes that express the CD4 receptor on their surface. This lymphocyte subpopulation is also referred to as T helper cells. Alongside viral load, measurement of the CD4 T cell level is the most important parameter or surrogate marker in HIV medicine. It allows for a reliable estimate of the individual risk of developing AIDS. All HIV-positive patients should have a CD4 T cell measurement every six months. Two reference values are generally accepted: above 400-500 CD4 T cells/µl, severe AIDS-related diseases are very rare; below 200 CD4 T cells/µl, the risk of AIDS-related morbidity increases significantly with increased duration of immunosuppression. Most AIDS-related illnesses occur below 100 CD4 T cells/µl.

Several points should be considered when measuring CD4 T cells (usually by flow cytometry). Blood samples should be processed within 18 hours. The lower normal values are between 400 and 500 cells/µl, depending on the laboratory. Samples should always be sent to the same (experienced) laboratory. The same applies for viral load as for CD4 T cells: the higher the level, the greater the variability. Differences of 50-100 cells/µl are not unusual. In one study, the 95% confidence intervals with a real value of 500 cells/µl were between 297 and 841 cells/µl. At 200 CD4 T cells/µl, the 95% confidence interval was between 118 and 337 cells/µl (Hoover 1993).

Measurement of CD4 T cells should only be repeated in the case of highly implausible values. As long as the viral load remains below the level of detection, there is no need to be concerned even with decreases in CD4 T cells. In such cases, the relative values (CD4 percentages) and the CD4/CD8 ratio (ratio of CD4 to CD8 T cells) should be referred to; these are usually more robust and less prone to fluctuation. As a general point of reference, with values above 500 CD4 T cells/µl, fluctuations of more than 29% are to be expected, with less than 200 CD4 T cells/µl fluctuations of less than 14%. Individual laboratories may define the normal ranges for the relative values and the ratio differently. If there are considerable discrepancies between absolute and relative CD4 T cells, any decisions involving treatment should be carefully considered – if in doubt, it is better to check the values again. The remaining differential blood count should also be scrutinized carefully – is leucopenia or leukocytosis present?

Clinicians sometimes forget that the result of the CD4 T cell count is of existential importance for the patient. To go to the doctor and discuss the test results can involve a great deal of stress for many patients. Insensitively informing the patient of a supposedly bad result can lead to further negative results. From the start, patients must be informed about the possible physiological and method-related variability of laboratory tests. In the case of unexpectedly good results, every effort should be made to contain euphoria. In the long run, this saves time and discussions, and the patient is spared unnecessary ups and downs. We do not consider it advisable for non-physician personnel (without extensive HIV experience) to inform patients of results.

 

Figure 2: Slow decline of the absolute and relative (dashed line) CD4 T cells/µl over almost ten years in a treatment-naïve patient. Note the variations in the absolute numbers.

Once CD4 T cell counts within the normal range are reached in addition to adequate viral suppression, measurements every six months should suffice, in our opinion. The probability of CD4 T cells dropping to values below 350/µl is extremely low in such cases (Phillips 2003). Patients who might sometimes insist on more frequent monitoring of immune status can be assured that there are usually no detrimental changes in the CD4 T cell count as long as HIV remains suppressed.

Influencing factors

Several other factors can influence CD4 T cell counts apart from laboratory-related variables. These include concurrent infections, leucopenia of varying etiology and steroids or other immunosuppressive therapies. Extreme exertion, surgical procedures or pregnancy can also lead to lower values. Even diurnal variation occurs; CD4 T cells are lower at noon, and highest in the evening around 8 p.m. (Malone 1990). Psychological stress seems to play a negligible role, even though patients often assume the contrary.

Kinetics of CD4 T cells on ART

Similarly to viral load, a biphasic increase in CD4 T cells occurs following the initiation of ART (Renaud 1999, Le Moing 2002), with a rapid increase within the first three to four months and a much slower rise thereafter. In a study of almost 1000 patients, the CD4 T cell count increased by 21/µl per month during the first three months. In the following 21 months, this rate was only 5.5 CD4 T cells/µl per month (Le Moing 2002). The initial rapid increase in CD4 T cells is probably due to redistribution, which is followed by the new production of naïve T cells (Pakker 1998). Diminished apoptosis may also play a role (Roger 2002).

It is still being debated whether the immune system steadily continues its recovery even after a long period of viral suppression, or whether a plateau is reached after three to four years beyond which there is less improvement (Smith 2004, Viard 2004).

Several factors can influence the extent of immune reconstitution during ART. The degree of viral suppression is crucial – the lower the viral load, the more pronounced the effect (Le Moin  2002). The absolute increase is higher if CD4 T cell counts were high at the start of ART (Kaufmann 2000). Naïve T cells still present at initiation of therapy are a particularly important factor for long-term immune reconstitution (Notermans 1999).

Age is also important (Grabar 2004). The larger the thymus and the more active the process of thymopoiesis, the more significant the rise in CD4 T cells is likely to be (Kolte 2002); due to age-related degeneration of the thymus, CD4 T cells in older patients do not increase as much as those in younger ones (Viard 2001). However, we have seen both 20 year-old patients with very poor CD4 T cell count recovery and 60 year-old patients with very good, above average increases in CD4 T cells. The regenerative capacity of the human immune system seems to vary considerably, and no method to date has been capable of reliably predicting this capacity.

It is possible that some antiretroviral therapies such as ddI+tenofovir are associated with less immune reconstitution than others. In addition, current studies evaluate if immune reconstitution is better during treatment with CCR5 antagonists. Immunosuppressive concurrent medications should also be considered (see chapter on Goals and Principles of Therapy).

Practical tips for dealing with CD4 T cells

  • As with viral load: use only one (experienced) laboratory.
  • The higher the values, the greater the variability (consider numerous factors) – compare the relative (percentage) values and CD4/CD8 ratio with previous results.
  • Do not disconcert the patient when there are apparent decreases – if viral suppression is sufficient, the drop is usually not HIV-related. Only highly implausible results should be repeated.
  • If the viral load is below the level of detection, three-monthly measurements of CD4 T cells are sufficient.
  • In the presence of good viral suppression and normal CD4 T cells, CD4 T cells (not viral load) may also be checked less frequently.
  • CD4 count and viral load should be discussed with the physician. Do not leave patients alone with their results.

Beyond the measurement of the CD4 T cell count and lymphocyte subpopulations, a number of other assays allow detailed testing of the qualitative or functional capacity of the immune system, for example in response to specific antigens (Telenti 2002). These often cumbersome methods are not currently necessary for routine diagnostics and their use remains questionable. However, they could one day help to better describe individual immune status and, for example, identify those patients who are at risk of developing opportunistic infections despite good CD4 cell counts.

Routine checks – What else should be monitored?

Besides the CD4 T cell count and viral load several other parameters should be monitored in the HIV-positive patient. The following recommendations apply to clinically asymptomatic patients with normal results on routine laboratory evaluation, who have been on stable treatment for several months or who are not taking antiretroviral therapy. Of course, if treatment is started or changed or if the patient develops complaints more frequent monitoring is required. Depending on the problem additional tests may be necessary.

A complete physical examination should be performed regularly, and this often leads to the discovery of important findings such as Kaposi lesions or mycoses (thrush). The lower the CD4 T cells, the more frequently patients should be examined.

In patients with less than 200 CD4 T cells/µl, we usually perform fundoscopies every three to six months to exclude CMV retinitis. Close cooperation with an HIV-experienced ophthalmologist is essential. The better the CD4 T cells, the less often fundoscopies are necessary – in our opinion when CD4 counts have normalized these can be stopped completely. In contrast, regular gynecological examinations with PAP smears are recommended regardless of CD4 count. Many experts now also recommend rectal examination (including proctoscopy) for the early detection of precancerous lesions and anal cancer.

However, such guidelines or recommendations can be interpreted very differently. In our opinion in cases of good immune status unless there is a specific suspicion routine X-rays, ultrasound examinations (exception: patients with chronic hepatitis, as hepatocellular carcinoma is not rare in such cases), multiple serologies or lactate measurements are not necessary. An annual ECG is only indicated in our view in patients with a specific risk profile (see chapter on HIV and Cardiac Disease). The tuberculin test (the Mendel-Mantoux skin test with 5 IE once a year) should only be repeated if it is negative initially.

Table 11.2. Minimal evaluations per year in stable asymptomatic patients.
 

Patient on ART

per year

Untreated

per year

Blood count, LDH, ALT, AST, creatinine, bilirubin, AP, lipase, GGT, glucose

4-6 x

2-4 x

Viral load

4 x

2-4 x

CD4 T cells

2-4 x

2-4 x

Lipids

1-2 x

1 x

Physical examination, urine status

2-4 x

1-2 x

Gynecological examination

1 x

1 x

Funduscopy if CD4 T cells <200/µl

1-2 x

4 x

With regard to the growing age of the HIV population, it is essential not to forget cancer screening. In many countries, for example, colonoscopy is recommended for early detection of colorectal cancer for every individual older than 50-55 years (colonoscopy should be performed every 10 years). For further information see WHO website, http://www.who.int/cancer/detection/en/

Therapeutic Drug Monitoring (TDM)

Plasma levels of many antiretroviral drugs may vary considerably for diverse reasons (e.g., compliance, metabolism, absorption). Measurement of drug concentrations in serum or plasma is also referred to as therapeutic drug monitoring (TDM).

Sufficient plasma levels are essential for success of virologic treatment (Acosta 2000). In the VIRADAPT Study adequate PI concentrations were even more crucial than knowledge of resistance mutations (Durant 2000). The importance of sufficient plasma levels has also been shown for NNRTIs (Marzolini 2001, Veldkamp 2001). This information however dates to the early years of ART.

Whether TDM still improves virologic response today, is not clearly validated (Kredo 2009). Only a few large randomized studies exist that have provided data regarding this question (Review: Liu 2010). One of the few randomized studies could only show a trend to virologic (Best 2007). TDM remained without any effect in another study with patients receiving boosted PIs (Demeter 2009).

On the other hand, very high plasma levels correlate with a higher rate of side effects. Reported renal problems with indinavir (Dielemann 1999), gastrointestinal disturbances with ritonavir (Gatti 1999), hepatotoxicity with nevirapine (Gonzalez 2002) or CNS problems with efavirenz (Marzolini 2001) were all associated with high plasma levels. For this reason, TDM will remain a tool for therapy observation: not every interaction between antiretroviral drugs or with concomitant drugs has been investigated.

Measurement of plasma levels may currently be reasonable in the following situations (German-Austrian ART guidelines):

  • Complex drug combinations including boosted PIs
  • Patients with very high or low body weight
  • Side effects
  • Treatment failure (resistance?)
  • Suspected absorption or adherence problems
  • Severe liver or renal diseases
  • Art with children, pregnancy
  • Once daily regimen
  • Use of new drugs (unknown interactions)

Several problems associated with TDM limit its broader use. The measurement of NRTIs, for example, is not possible since they are converted to the active metabolites only intracellularly. Intracellular measurements are difficult and are not available in routine clinical practice. There is no valid data available for new antiretroviral agents such as T-20, raltegravir or maraviroc.

Measuring NNRTIs or PIs may therefore currently determine levels of only one component of a failing combination. Further problems include not only viral strains with different levels of resistance, different inhibitory concentrations, variable protein binding, and time-dependent variability of plasma levels, but also methodological problems with the assays, as well as the lack of clearly defined limits. Many uncertainties thus remain in the assessment of therapeutic drug plasma levels. Until data from randomized studies is available, proving the clinical value of TDM, both the measurement and interpretation of results should be left to specialized centers.

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Filed under 6.11. Monitoring, 6.9. Salvage Therapy, Part 2 - Antiretroviral Therapy

6.12. Prevention, compliance, costs

– Christian Hoffmann –

In the following, some aspects of antiretroviral therapy will be discussed in more detail that have only been mentioned briefly in previous chapters.

Prevention

About 30 years after AIDS was first described a prophylactic vaccination remains a distant prospect. In 2007 two highly promising vaccine studies were prematurely interrupted. It seems doubtful now that a vaccine to effectively prevent HIV infection will be discovered anytime soon – the moderate but surprisingly successful RV144 vaccine study will not change that (Rerks-Ngarm 2009, see chapter on Preventive Vaccination). Several experts believe that a promising vaccine candidate does not exist presently (Desrosiers 2008, Nathanson 2008) while others say it is time to get used to the fact that a vaccine may never come. Neither blind hope nor time schedules have proved very helpful. Some vaccine studies up until now can in fact be regarded as counter-productive, fatiguing both sponsors and the community.

Considering all this, prevention will continue to be the central means of controlling the HIV epidemic. However, common prevention strategies focused on the ABC guidelines (abstinence, be faithful, condom use) have reached their limits. In 2009 UNAIDS declared a worldwide increase of 2.2 million new infections. In every major city in the US or in Europe syphilis endemics in HIV-infected patients have been reported. In Germany, for example, the number of new infections among men who have sex with men (MSM) has been almost continuously rising since 2001.

It seems clear that advertisements and brochures alone are not the solution, especially when these simple publicity mechanisms are not maintained. High-risk groups are not being reached effectively. Prevention remains an arduous business and success is not immediately visible nor is it profitable. Sexual behavior is not easily modified by a few advertisements or brochures.

For some time, preventive medicine in HIV has been taking completely new and sometimes unusual paths to reach focus groups. Terms such as serosorting, seropositioning, dipping or strategic positioning show that the medical world is learning to face reality. People have sex and not everyone cares about, follows, or can follow guidelines. Recent studies with serosorting, choosing sexual partners according to perceived HIV serostatus, show that new prevention strategies can be developed (Morin 2008).

The following focuses mainly on medical prevention strategies. In 2010 there have been groundbreaking new findings in this area regarding PrEP and microbicides.

ART & Prevention

Antiretroviral therapy is an important contribution to prevention, possibly the most important (Hosseinipour 2002). As these studies show:

  • In a group of 415 HIV-discordant couples in Uganda 90 new infections were diagnosed over a period of 30 days. Not a single infection was caused by an infected partner with a viral load below 1500 copies/ml. With every additional log of HIV RNA, infection risk increased by a factor of 2.45 (Quinn 2000).
  • In a study in Thailand with 493 HIV-discordant couples, the factor was 1.81. No infection from a partner with less than 1094 copies/ml was recorded (Tovanabutra 2002).
  • In a study in Spain with 393 heterosexual HIV-discordant couples, a transmission rate of 8.6% was observed between 1991 and 2003. No infection was recorded with infected partners who were receiving combination ART.
  • In a group of 534 MSM in San Francisco, infectiousness based on the probability of transmission per couple decreased by 60% between 1994 and 1998 (Porco 2004). The HIV incidence decreased in spite of the reported higher number of partners and risk contacts, even though not all of the HIV-infected partners were on antiretroviral therapy.
  • In a Spanish study with 62 HIV-discordant couples (22 HIV-infected women, 40 HIV-infected men, all of them on ART), 76 “natural” pregnancies were diagnosed. Not a single HIV infection of a non-infected partner was recorded (Barreiro 2006).

The above-mentioned clinical studies show clearly that the lower the viral load in the plasma, the less infectious the patient. In an ongoing meta-analysis in 11 cohorts with 5021 heterosexual couples (and 461 HIV transmissions) the transmission rate of patients on ART was 0.46 per 100 person years (5 cases). Not one transmission was detected from anyone who was below 400 copies/ml (Attia 2009).

Test and treat?

At the end of 2008 a statistical paper caused great discussion. A research group led by the Director of WHO Kevin De Cock calculated how to, at least theoretically, curtail and even eliminate the worldwide HIV epidemic (Granich 2008). For this ambitious goal they concentrated totally on the preventive effect of antiretroviral therapies. They compared the common treatment strategy used today, beginning ART only on symptomatic patients or on those who have less than a certain number of CD4 T cells, to a theoretical strategy that seems simple enough. Every person is tested for HIV once a year and if found positive, starts ART immediately, irrespective of CD4 T cells or viral load. The study was based on population data in South Africa, where 17% of the adult population is HIV-infected and on data from a successful intervention in Malawi. Other preconditions of the calculation model are that infectiousness of treated versus not-treated patients was estimated at 1%. The case-reproduction number, the so called R0 number of new infections caused by one infection, was crucial for this calculation. The corresponding simple assumption that R0 of <1 is required in order to reduce the incidence and to eventually eliminate HIV means that an incidence rate of less than one new case per 1000 person years was determined in order to eliminate HIV.

Reality shows different results. At present, every untreated HIV-infected individual causes another 7 HIV infections (R0=7) in the course of their lifetime. R0 could be reduced to 4 if every person received regular treatment with therapy starting at 200 CD4 T cells/µl, or even to 3 if therapy starts at 350 CD4 T cells/µl. However, an R0 reduction to less than 1 is impossible by this method and curtailing the epidemic with ART alone remains unrealistic. This could change however, with regular testing and immediate treatment of positively-diagnosed individuals – elimination of the epidemic could be possible by 2020, even in a country as severely affected as South Africa. Compared with common practice today where ART is begun only at a certain level of CD4 T cells, immediate treatment could reduce AIDS mortality to half today’s number by 2050. Calculations showed that this initially more expensive strategy could start to be cost-saving by around 2032.

The comments to the WHO publication ranged from “provocative” (Cohen 2008) to “extremely radical” (Garnett 2008). Critics raised concerns over the risks and the absence of ethics (would all actors agree? Could a restricted individual autonomy be achieved? Can changes in sexual habits be maintained?), medical (compliance problems, the dangers of possible resistance, the side effects and “overtreatment” – starting too early) as well as financial (South Africa would have to triple their financial commitments) considerations.

Such calculations are not new. Other groups have arrived at similar results in the past (Velasco-Hernandez 20002, Montaner 2006). What is new is that antiretroviral therapies today are potentially more user-friendly and such programs are probably easier to put into practice than just a few years ago.

In addition, people are realizing that the current preventive measures can only improve slowly and that neither vaccines nor microbicides can be expected in the near future. At present, approximately 80% of the population in sub-Saharan Africa is not aware of their infection. More than 90% do not know if their sexual partners are infected – an invitation for further spread of the epidemic.

Juggling figures like this may seem unhelpful at first. Despite all objections regarding methodological, ethical, financial or logistic considerations, etc., facing 2.2 million new infections per year, a number that is not likely to decline much (if at all) in the near future, and the failure of several vaccine and prevention studies, one thing has become clear. Antiretroviral therapy has turned into one of the most important components of prevention.

Such initiatives like that of the WHO must be continued, and new and unusual strategies must be continually developed. It cannot do harm to bring more therapy to the 6.7 million people, worldwide, the number who by the end of 2007 desperately needed ART and were not receiving it (see chapter on Global Access).

ART & viral load in other body fluids

Do viral load in plasma and viral load in other body fluids correlate?  Here are some data:

  • In a study from Italy the viral load on PI-containing ART regimens decreased by several logs in plasma as well as in semen (Liuzzi 1999).
  • In a Swiss study with 114 male patients with plasma viremia under 400 copies/ml on ART, only 2 (2%) isolated viral loads were detected in semen, compared to 67% in untreated control groups.
  • In 205 HIV-infected women with plasma viremia under 400, 400-9999 and over 10,000 copies/ml, the rate of detectable HIV-1 RNA in the genital tract was 3, 17 and 48%, respectively (Cu-Uvin 2000). In 7 ART-naïve women, the viral load decreased by 0.7–2.1 logs within the first 14 days of ART. Similar results were achieved with 11 Brazilian female patients (Vettore 2006).
  • In a group of 290 women with plasma viremia under 500 copies/ml, 44 (15%) had detectable HIV-1 RNA in cervical smears (Neely 2007). In comparison to PI-containing ART the risk with NNRTIs was double.
  • In a study with 34 females with plasma viremia below 80 copies/ml, all treated with ART for at least 6 months, only one woman showed a viral load over 80 copies/ml in cervical vaginal fluid (CVF) compared to 7 rebounds in plasma (Kwara 2008).
  • Out of 122 samples of cervical vaginal lavage the viral load in the lavage correlated highly with plasma viral load (Fiore 2003). However, in 25% of cases, virus was found in the lavage even when plasma viremia findings proved negative.
  • In a study with 233 MSM (1996–1997), far less virus was found in anorectal smears of those treated with ART. Among those patients with less than 50 copies/ml in plasma, 1/54 (2%) HIV-1 RNA was detected in the anorectal smear. However, in 14/50 (28%) HIV-1 DNA was detected.
  • Among 255 MSM receiving ART with a plasma viral load below 40 copies/ml, 7 patients (3%) showed an isolated viral load in semen (Marcelin 2009). These 7 patients had been on ART for some time and treated with agents detected in semen.
  • In a prospective study on 25 Canadian patients on ART, a viral load in semen was found in 19/116 (14%) samples (Sheth 2009). There was no reference to drug concentration  in seminal fluid.

In conclusion, in most cases, viral load in plasma parallels viral load in other bodily fluids. If the viral load in plasma decreases, so does the RNA in semen or the vaginal fluid within a short time. “Below the limit of detection in plasma” also means “below the limit of detection in other bodily fluids”. In most cases. There are exceptions: in the studies above the variation was between 1 and 14%. Although there are implications that the detected virus in semen is not completely infectious (Nunnari 2002), one cannot rule out the patient being potentially infectious even on successful ART.

Putting together these facts with clinical data, transmission with a low viral load seems unlikely. To date, only a few cases have been recorded in which transmission has taken place despite effective ART (Stürmer 2008). These cases show that there is in fact a residual risk. The question is how to manage that risk.

The EKAF paper

In January 2008 a paper was released by the “Eidgenössische Kommission für Aids-Fragen” (EKAF), the Swiss AIDS commission. Just the title of this paper caused a great stir: “HIV-infected individuals without other STDs on effective antiretroviral therapy are not sexually infectious.” The original manuscript can be found at http://www.saez.ch/pdf_d/2008/2008-05/2008-05-089.PDF.

EKAF concluded that HIV-infected individuals do not transmit the disease under three conditions:

1. ART is adhered to and monitored by a clinician

2. The viral load has been below detection for at least six months

3. There is no other STD

This first official statement from public authorities on this subject had a major impact. Despite its caveats, critics feared that this publication could be misunderstood as an all-clear signal resulting in people being less careful and unnecessarily exposing themselves to risks of HIV infection.

Critics say that the data is not sufficient, especially for the risk of anal sexual contacts. The probability of infection is certainly under 1:100,000, but nevertheless not zero (Wilson 2009). The preventive effect of ART may be endangered by higher risk taking. According to mathematical models, a 10% rise in risk behavior could counter the effects of ART (Blower 2001, Law 2001). However, a meta-analysis came to the conclusion that ART does not increase risk behavior of the patient, even if the viral load is below detection (Crepaz 2004).

HIV clinicians must be prepared for this discussion. Patients are asking more questions: do I have to use a condom for the rest of my life? Here, it is better to give individualized advice. It depends greatly on the non-infected partner as well, as he or she should not be pressured. On the other hand, information of this type can be a relief for many patients and their partners. The EKAF paper may also motivate high-risk patients to finally start antiretroviral treatment (preventing more infections rather than causing new ones initially feared by the release of the paper).

However, it must be repeated that the EKAF statement refers only to stable relationships. Safer sex is still recommended, especially with occasional sexual contacts to avoid other sexually transmittable diseases.

Medical prevention strategies besides ART

Circumcision

Circumcision of the male foreskin reduces the risk of infection for several diseases in unprotected sexual intercourse (Weiss 2006). At least three randomized trials with heterosexual males in Uganda, Kenya and South Africa demonstrated this in recent years for HIV as well. Remarkably similar results were achieved (Table 12.1).

Table 12.1. Large randomized studies on circumcision.
Place

Reference

n

Main Results

Reduction of Transmission risk

Kenya
(Bailey 2007)

2784

Two–Year HIV Incidence 2.1%  (95% CI 1.2-3.0) vs 4.2% (95% CI 3.0-5.4)

53-60%

Uganda
(Gray 2007)

4996

Over 24 months HIV incidence
0.66 vs 1.33/100 person years

51-60%

South Africa
(Auvert 2005)

3274

Over 18 months HIV incidence
0.85 vs 2.10/100 person years

60-61%

TR = Transmission Risk, partly different definition/calculation

A meta-analysis of these studies shows a relative risk of 0.44 for circumcision (Mills 2008). The NNT (number needed to treat) required to prevent an event reached a relatively low number of 72.

The effect of circumcision is explained by the presence of CD4-positive Langerhans cells and primary HIV target cells in the male foreskin. Circumcision reduces the frequency of genital HSV-2 infection (Tobian 2008), which however does not explain the protective effect (Gray 2009). An estimated 2 million HIV infections in Africa alone could be prevented in the next few years (Williams 2006). The WHO recommends circumcision as a preventive means for heterosexual men. A favourable side effect is that fewer HPV-infections are transferred (Serwadda 2010)

Circumcision, however, is not without risk. Complications (infections, postoperative bleeding) occur in 3-4% of cases (Gray 2007). Sexual behavior after circumcision, ethics and logistical problems are only a few aspects (Lie 2006). It must be noted that circumcision reduces the risk for male but not for female partners. The randomized study in Uganda showed a slight increase in infections of the female partners of circumcised males (Waver 2008). This can be mainly explained by couples probably having sexual intercourse earlier than recommended. Several weeks of no-sex are stipulated after the operation.

Is there a protective effect for MSM after circumcision? If there is, the data is less clear compared to the results for heterosexual men. A meta-analysis of 15 greatly varying studies with 53,567 MSM (52% with circumcision) showed no significant difference between circumcised and uncircumcised males (Millet 2008). Another newer study confirms these results (Sanchez 2011).

Preventive treatment of HSV and other diseases

Genital infections clearly increase the risk of acquiring HIV. This applies especially to the human herpes virus 2 (HSV-2). According to a meta-analysis, the risk of HIV increases with HSV-2-seropositivity: when HSV-2 antibodies are detected in the blood, the risk increases in male patients by 2.7 fold and in female patients by 3.1 fold (Freeman 2006). A considerable amount of new HIV infections are due to HSV coinfection, with an estimated 38–69% in female patients and 8–49% in male patients.

Is a reduction of the HIV transmission rate in HIV-negative persons possible by suppression of HSV-2? HPTN 039, a double-blind, randomized, Phase III trial investigated (Celum 2008). In total, 1871 MSM from the USA and Peru and 1380 women from Zimbabwe, Zambia and South Africa received 400 mg acyclovir or placebo twice daily. Enrolled subjects were all HIV-negative and HSV-2-positive at the beginning of the trial. Although less HSV ulcers were observed in the active group, the trial failed to show a decline in HIV incidence in the acyclovir-group, with 3.9/100 person-years compared to 3.3/100 in the placebo group. These disappointing results were confirmed by the Mwanza trial with 821 women in Tanzania, in which again no decline was observed (Watson-Jones 2008). It is still not clear why, however, resistances against acyclovir is unlikely (Watson-Jones 2010).

According to current data, preventing HIV infection with HSV therapy using acyclovir has proven unsuccessful. The prophylactic use of azithromycin, to prevent bacterial STDs also showed no protective effect against HIV (Kaul 2004).

Can the transmission rate be reduced if the HIV-infected partner is treated with acyclovir? A huge study enrolling 3408 discordant African couples showed no effect of the transmission rate, albeit the clearly reduced rate of genital HSV ulcers (Celcum 2010). However, this study did show an interesting side effect, that there is a slight but measurable effect with acyclovir and its derivatives regarding HIV viral load. Compared to placebo, a decline of 0.25 logs was observed. This effect slightly decreased the risk of HIV progression in therapy naïve patients (Lingappa 2010). The transmission rate was obviously not influenced by the reduction in viral load. Resistances were not induced by acyclovir (Baeten 2011).

Antiviral effects were also observed in several other randomized studies. The viral load in blood and cervicovaginal fluids was reduced by 0.26 to 0.53 logs by using acyclovir or valacyclovir (Delany 2009, Nagot 2007, Zuckermann 2007, Baeten 2008, Dunne 2008, Paz-Bailey 2009). These studies may possibly lead to the development of new acyclovir derivatives with improved antiviral potency, provided they respond well to HIV (Vanpouille 2010).

Microbicides, lubricants, diaphragms

Microbicides are chemical agents, mostly of topical application, in the form of gels that kill or immobilize HIV and other diseases. Presently heterogenic mechanisms are being examined. Among them are inactivated agents that inhibit docking to the target cell or antiviral agents. It is required that microbicides are not only inexpensive, easy to apply and non-toxic, but also effective against other STDs, as these increase the risk of HIV-transmission. The CAPRIAL trial (see below) has led to a noticeable revival in this field of research.

Inactive microbicides: Up to now, there is no product that has delivered convincing protective effects in clinical studies. HIV transmission risk in fact increased with nonoxynol-9 (Van Damme 2002) or cellulose sulfate (van Damme 2008).  PRO 2000, which initially seemed promising, had no effect (McCormack 2010). Application of diaphragma and/or lubricants in addition to condomes had no protective effect, as one randomized study showed (Padian 2007).

Antiretroviral Microbicides: A breakthrough in research of microbicides was achieved in the CAPRISA trial in September 2010. CAPRISA was a doubleblind study, in which 889 HIV-negative women in South Africa used 1% tenofovir gel (Abdol Karim 2010). Compared to placebo, HIV incidence was reduced from 9.1 to 5.6/100 years. Transmission risk for women applying the gel regularly was reduced by 54%. This first success (“proof of concept”) has led to a focus on antiretroviral substances in the research of microbicides, such as tenofovir and even the more experimental NNRTIs dapivirine and MIV-150, as well as maraviroc and raltegravir (Review: Mertenskötter 2011).

PrEP (Pre-exposure Prophylaxis)

In the HIV setting, PrEP is an oral prophylactic antiretroviral treatment. Like malaria prophylaxis, it is taken before exposure. PrEP trials are currently being conducted in high-risk groups (i.e., commercial sex workers). Most trials use tenofovir, either alone or in combination with FTC. Such studies, however, have been regarded with criticism. Pressured by activists and others, a study with Cambodian sex workers was interrupted in 2004 and others in Cameroon and Nigeria in 2005 (Cohen 2004, Sing 2005). The researchers involved were accused of not providing sufficient information to the participants and of discontinuing treatment once the study was over.

A similar breakthrough, like the one with microbicides by the CAPRISA trial, was seen with PrEP in the end of 2010. In the iPrEx study, 2499 MSM from six countries received either TDF+FTC or placebo. After a median of 1.2 years, 36 versus 64 infections were observed and the risk for infection was reduced by 44%. Apart from slightly more cases of nausea and weight loss in the verum group, there were no differences. Only in 3/34 patients infected in the verum group, tenofovir or FTC were detected in plasma. One may argue that complete protection is not secured: However, with an alarmingly high number of 2.2 million new infections worldwide, PrEP remains an approach that must be pursued.

Table 12.2: Large randomized study on PrEP, March 2011
Country

n

Risk group, kind of  PrEP

Status, first results

Thailand

2.400

IDU: tenofovir

fully recruited, 2012

Africa, Partners PrEP Study

4.758

discordant couple: tenofovir, Tenofovir+FTC

fully recruited, 2012

Africa, FEM PrEP

3.900

women: tenofovir+FTC

49 % recruited, 2013

Africa,  VOICE/ MTN 003

5.000

women: tenofovir, tenofovir+FTC, vaginal tenofovir gel

65 % recruited, 2013

Physicians must be prepared for inquiries on PrEP, although some questions still remain that have not been answered by the above study.

How should PrEP be administered? Who will receive the treatment? And who will cover the expense? What about development of resistance in unidentified HIV infection? Will this decrease the use of condoms? Will PrEP be sold on the black market in the near future (and so, with limited adherence programs)? These are only a few aspects to be considered. In Switzerland as well as at the EMA, a commission dealing with these questions has already been set up, although the benefits of PrEP have not yet been scientifically proven.

In conclusion, with dramatically high numbers of continuing infections worldwide, prevention must strike new paths. Strictly Propagating safer sex alone is not enough. Among medical approaches, the use of antiretroviral therapy is the most imaginative strategy right now. The EKAF paper will continue to be discussed. Like it or not, microbicides and PrEP will have a lasting effect on HIV prevention. Patients will be asking for it.

Compliance

Compliance is the Achilles’ heel of every antiretroviral therapy and non-compliance the main, if not the major factor for developing resistance and treatment failure (Turner 2000). Partial viral suppression with insufficient drug levels is ideal conditions under which resistance grows. There is no doubt – ART must be taken regularly, correctly or not at all. Taking either more than 90% or less than 69% of the treatment are both associated with a lower risk of resistance (Sethi 2003). Compliance is defined as a patient’s consent and acceptance of therapy. In the mid-90s a new term “adherence”, from the English language, was adopted. Since then, the more politically correct term – “adherence” is frequently used. This term refers to both physician and patient working together to set up a treatment concept acceptable to both parties and emphasizes that responsibility for a failure of the therapy is not only the patient’s fault.

Adherence includes all factors that influence staying on a regimen, in terms of acceptability. Whichever term is used, three facts remain:

  1. The success of a treatment is endangered if medication is taken irregularly
  2. Clinicians tend to overestimate a patient’s compliance
  3. Compliance diminishes with the complexity of the treatment

Not only drug consumers, those dependent on alcohol or patients with side effects are considered “risky patients” when it comes to adherence. In several studies, depressed patients, patients living alone and younger patients have been identified as problem groups (Murri 2001, Frank 2002, Glass 2006). Positive factors are the physician’s experience, the patient’s confidence in the positive effects of ART, and social support. Race, sex or stage of disease does not seem to be relevant. The individual’s general view of illness and health, accepting modern medicine and fear of side effects are further considerations. However, all these factors vary greatly, and in the end, adherence is difficult to predict in individual cases (Lerner 1998). The physician must rely on experience and intuition.

The importance of taking drugs regularly has been demonstrated in numerous studies. In one study with 99 patients, in which compliance was evaluated via an electronic monitoring system, the rate of viral treatment failure was only 22% in patients with a compliance level of at least 95% (95% of doses taken). Failure rates of 61% and as much as 80% were measured with a patient’s adherence between 80-94% and < 80% (Paterson 2000). However, it must be taken into consideration that this much-cited study is outdated. Newer drugs, such as darunavir, with longer half-lives, higher resistance barriers and better overall pharmacokinetics may forgive a clearly higher non-compliance (Nelson 2010). In the previously mentioned study, clinicians misjudged their patient’s compliance in 41% of the cases. Nurses did better – judging incorrectly in only 30% of the cases (Paterson 2000). Adherence tended to be overestimated in other studies as well (Miller 2002). The importance of adherence was demonstrated in patients with directly observed therapy (DOT) or directly administered ART (DAART), applied in some penal institutions in the USA. In institutions in Florida, 100% of the patients in a DOT study achieved a viral load below 400 copies/ml after 48 weeks, compared to 81% in an unmonitored control group (Fischl 2001). According to one randomized study, response improved in drug-addicted patients receiving DAART (Altice 2007). More recent data indicate that effects of PI based regimen (given as DAART) are marginal and disappear rapidly as soon as the patient is on his own (Gross 2009).

Poor compliance not only leads to virologic failure. It also bears immunological consequences. In an analysis of two prospective studies, patients with a compliance of 100%, 80-99% and < 79% experienced a reduction in viral load by 2.77, 2.33 and 0.67 logs after a year. At the same time, the CD4 T cell count increased by 179, 159 and 53 cells/µl, respectively (Mannheimer 2002).

Moreover, poor adherence has clinical effects beyond surrogate markers. In a Spanish study, patients who did not take more than 10% of their drugs showed a four-fold increase of mortality risk (Garcia 2002). This data has been confirmed in other studies (Maher 1999, Hogg 2000, Wood 2004). Hospital stays are also less frequent in patients with high adherence to ART (Paterson 2000). In addition, it should be considered that non-adherent patients increase the risk of transmission of primary resistant viruses. The basic mechanisms for development of resistance should be explained to patients. One must emphasize that, in contrast to other chronic illnesses, resistance mutations do not disappear once they have developed. Diabetes and hypertension make effective examples. These diseases may “tolerate” forgetting some tablets occasionally, but HIV is different. Blood glucose and blood pressure levels can easily be lowered again the next day, but with HIV this strategy may not work. Even short-term lapses can have irreversible consequences. And every new occurrence of resistance complicates therapy. Patients have to be made aware of these dangers. Such conversations should be repeated from time to time and become a standard component of routine care. Cooperation with special treatment discussion groups offered by patient-centered support organizations can be useful. The 12-step table below provides additional suggestions. In addition, a number of strategies on improving adherence have been investigated. They range from employment of additional nurses to telephoning patients regularly. This last one, telephone reminders, appears to not have an influence on compliance (Collier 2005).

If adherence remains poor

Despite all efforts, some patients will not succeed in improving their adherence. Physicians and other healthcare providers should not take this personally or feel offended should a patient not want to participate in the advances of medicine. Although it may be difficult to accept the patient’s views on life, disease and treatment, healthcare providers must keep tolerance and acceptance as key components in their interactions with patients. Some providers, especially those who treat selective patient populations in university settings, tend to forget the reality of routine medical practice. Rigidly upholding the principles of modern medicine usually does not help here and putting patients under pressure achieves even less. It is important to clearly outline and explain, advise, help, question and listen.

The question of whether noncompliant patients should continue to be treated with antiretroviral therapy is not always easy to address. On the one hand, there are patients who benefit even from suboptimal therapy; on the other hand, drugs are expensive and should not be prescribed too readily. When resources are limited, available drugs should be distributed with care. Restraint should be applied until the reason for poor compliance is understood.

Twelve steps to improve compliance

  1. Every patient should receive a written (understandable by the patient) treatment plan, which should be reviewed at the end of the visit. It should include a telephone number to call in case of problems or questions, accessible evenings and weekends would be even better.
  2. Patient and clinician should agree on the treatment plan. The patient’s concerns, questions and criticisms should be discussed.
  3. The patient should have the impression that the treatment regimen is not randomly chosen, but tailored to his/her individual needs.
  4. The explanation of a new or modified treatment plan takes time, and should not be rushed – all questions should be answered.
  5. The reasons why adherence is so important should be explained. It makes sense to repeat such conversations – they should not only take place when initiating or modifying treatment, but should be part of routine care.
  6. Possible side effects should be explained, as well as what can be done to alleviate them.
  7. Support groups and other types of assistance should be named and offered.
  8. It is important to tell the patient to come back if any problems are encountered with ART – it is better to try to solve them together than have the patient try to deal with them alone at home.
  9. The patient should know that the treatment regimen must be taken in its entirety (avoid, “Last month I left out the big tablets”).
  10. Prescriptions should be documented, in order to get a rough idea of adherence. Irregularities should be addressed openly. Pills counted, bottles checked?
  11. During all stages of therapy, the patient should be informed of treatment success as seen by reduction of viral load and rise in CD4 count.
  12. Ensure clinical vigilance to detect the early signs of depression and treat appropriately.

Duesbergians – a sect of HIV medicine

Patients who principally refuse antiretroviral treatment form a special case. These patients are frequently under treatment by (shockingly misdirected) doctors, who call themselves “Duesbergians” (after the US virologist and AIDS dissident Peter Duesberg, who denies any association between AIDS and illness). In such cases, it can be very difficult to leave patients to their fate. Informative consultations should be as detailed as possible and preferably documented in writing. Below, an example:

An approximately 40-year-old patient with a long history of untreated HIV, 30 CD4 T cells/µl and cerebral toxoplasmosis (TE), which improved significantly after 4 weeks of acute treatment (the last MRI still showed scattered lesions) introduced his case to the HIV outpatient department. Clinically, he was relatively well and fully oriented and due for discharge that day. In a conversation, the patient categorically refused to start the urgently recommended antiretroviral therapy. His Duesbergian physician had advised him against HIV therapy (“You can die from AZT, and the other drugs are not much better, etc”). He refused antibiotics on principal as well. This was why the patient would not continue the TE maintenance therapy, which had made him suffer from diarrhea (NB, probably cryptosporidiosis), skin problems (seborrhoic dermatitis, thrush), and extreme loss of weight (MAC?) since his first day in hospital. It was very important for him to have a break from all medication.

In such cases, we make sure the patients sign the information sheets. Every patient is allowed to and should decide for himself (if fully cognizant and capable) – they must know and be fully informed about what they are doing. It is important to give the patient control: if they changes their mind, they may return!

In our experience, arguing with medical Duesbergians leads to nothing at all. This sect has a very restricted view of the world and stick to their repetitive –mantra-like arguments. Discussing with them is time consuming and a waste of energy.

Fortunately, these cases have become rarer. The initial widespread scepticism towards ART has decreased significantly, due to its overwhelming success in the last few years. Concerning Peter Duesberg, it has become quiet, at least as far as his HIV activities goes. The sect is in decline.

Costs

Antiretroviral treatment is expensive. A health provider needs to be informed about costs for drugs.

In Germany, for example, the price for individual drugs range between €300 (Epivir®) and over €2,400 (Fuzeon®) per month, common threefold therapies range between €14,000 and €24,000 per year. Even within drug classes, there are astonishing differences. Crixivan® (hardly used today) is relatively cheap, while Aptivus® is more than three times the price. Even within primary therapies recommended in guidelines there are great price variations: PIs are almost double the price of NNRTIs in many countries. In Germany, annual costs for Kivexa®+Sustiva® are €6,400 cheaper than for Truvada®+Prezista®/r. If the integraseinhibitor Isentress®, the most expensive drug licensed for primary therapy is used instead of Prezista®,the difference is almost € 8.800 per year. A salvage therapy for a patient with multiresistant virus can amount to as much as €50,000 and more per year. Even though prices alone should not influence the choice of therapy, it is still important for the physician to be aware of the costs.

It is difficult to comprehend the price policy intended by pharmaceutical companies. The reason why prices for directly competing agents (3TC and FTC) are almost exactly the same, whilst prices for other agents of the same drug class differ by 200-300%, cannot be explained by development costs alone. There is no doubt. People are making money with ART and the market is full of competitors – monopolies and patents are being protected.

Despite all the criticism and price discussions, two facts can not be forgotten:

First, the high development costs for new medicines can rise to a billion dollars or more. Most agents never make it to the market. Even a licensed drug such as T-20 may never recoup its development costs. According to Roche, development and research alone chewed up 600 million dollars. To cover such production costs, thousands of patients worldwide would have to be treated with T-20 for several years – a very unrealistic scenario.

Second, there is hardly a more effective therapy than antiretroviral therapy. US estimations assume an expenditure of between $13,000 and $23,000 per additional QALY (quality-adjusted life year) (Freedberg 2001). Compared to many other therapies this is relatively cheap. ART reduces the cost of expensive treatment of opportunistic infections, inpatient and outpatient care. In one German study, between 1997 and 2001 total annual spending per patient decreased from €35,865 to €24,482 (Stoll 2002). Many patients return to work, resulting in an overall economic gain for society (Sendi 1999).

Nevertheless, ART is expensive. Therefore, it should be expected from patients to use up remaining packets of drugs, etc. if the reasons for a change in therapy are not urgent. Concerns of pill reduction or doubts about long-term toxicity should be part of an ongoing discussion with patients. All patients need to be made aware of the costs of medication –to make them aware of the value of the therapy.

Initially, ART should be prescribed for a month. This way, mountains of unused pills will not be wasted, if signs of intolerability or complicated adverse events set in. If response to ART is positive and its effects constant, prescriptions can then be done for a period of three months.

Many companies now offer three-month supply packages. This practice has not been without criticism. In any case, prescriptions of longer than a three months supply should be avoided.

In the future, we all need to be more aware of the costs for ART. The patents for AZT, ddI, 3TC, d4T and abacavir, but also saquinavir will disappear or have already gone. Efavirenz and nevirapine will soon follow. It will be interesting to watch price developments when generics come to the market, as they have in resource-limited settings

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Filed under 6.12. Prevention, compliance, costs, 6.9. Salvage Therapy, Part 2 - Antiretroviral Therapy

6.13. Global Access to HIV Treatment

– Rob Camp –

We all know this data, and we gloss over it every time we go to an international meeting:

•  Some 7,000 people become infected with HIV every day.

•  Approximately 5.25 million people are currently receiving ART, while at least 14.6 million people are still in need.

•  For every 2 people put on treatment, 5 more become infected.

•  With universal access, approximately 6.7 million people would receive life-saving ART, 2.6 million new infections could be averted and 1.3 million lives saved. Based on global goals and targets for 2015, it is estimated that an investment of US$25.1 billion/yr will be required for the global AIDS response in low- and middle-income countries (www.who.org, accessed 19.04.10).

In the developing world, the price of ART has fallen drastically in recent years. Even so their cost remains an obstacle to access for many millions. Moreover, the health infrastructure required to deliver ART and maintain adherence is lacking in many places. Access to drugs depends not only on financial and human resources. It depends also on people being aware of their HIV status, knowledgeable about treatment, and empowered to seek it. Thus public information and education are important elements in widening access, alongside efforts to build or strengthen health services. Stigma has been and remains a major stumbling block in wanting, seeking and taking the treatment regimen correctly. The campaign for universal access to life-saving drugs for HIV and AIDS, started originally by grassroots AIDS activists, is today a major focus of attention of UN agencies and other influential organizations at national and global levels.

The Declaration of Commitment on HIV/AIDS, unanimously endorsed by the UN General Assembly in 2001, embraced equitable access to care and treatment as a fundamental component of a comprehensive and effective global HIV response. Since then many countries, through the support of intergovernmental organizations and donors, have definitively demonstrated the ability to deliver HIV treatment in very resource-limited settings. Access to treatment has helped mobilize communities in response to HIV, preserved the health and viability of households vulnerable to HIV, and strengthened HIV prevention efforts in many parts of the world.

In the goal to reach universal access to HIV prevention, treatment, care and support, leadership at national level is required to establish policies that support treatment scale-up by:

•  increasing the number of people who choose to know their HIV status;

•  reducing HIV stigma;

• building human capacity to sustain treatment through training and better use of current human resources;

• improving supply management and integrating HIV care with other health services.

In 2011, the international community recommitted to the goal of universal access. This time, countries committed to achieving universal access by 2015. The goal of universal access is also part of Millennium Development Goal (MDG) 6 which includes the goal of halting and beginning to reverse the spread of HIV/AIDS by 2015.

The updated 2011-2015 global health strategy was released in June 2011. This strategy outlines four key targets that countries need to achieve if universal access and MDG 6 are to be realised: reduce new infections by 50 percent among young people (15-24 years), reduce TB-related mortality by 50 percent, eliminate new infections in children, and reduce HIV-related mortality.

Major Players

PEPFAR Update

The President’s Emergency Plan for AIDS Relief (PEPFAR) was launched in 2003 to combat global HIV/AIDS, and is the largest commitment by any nation to combat a single disease in history. During PEPFAR’s initial phase covering 2004-2008, the United States invested nearly $19 billion in PEPFAR (defined to include bilateral HIV/AIDS and tuberculosis programs, as well as contributions to the Global Fund to Fight AIDS, Tuberculosis and Malaria). For FY 2011, $5.56 billion was enacted for bilateral HIV/AIDS programs, $1.05 billion for the Global Fund; the line item for bilateral TB programs has not been agreed upon yet.

PEPFAR and the fight against HIV/AIDS is now the cornerstone of the US Global Health Initiative, which commits $63 billion over six years to support countries in improving and expanding access to health services. As part of the Global Health Initiative, PEPFAR is moving from its initial emergency focus to a heightened emphasis on sustainability, and serves as a platform for expanded responses to a broad range of global health needs. Through its partnerships with 31 countries, as of September 2010, PEPFAR directly supported ART for over 3.2 million men, women and children. PEPFAR partnerships have directly supported care for nearly 11 million people affected by HIV/AIDS.

In 2010, PEPFAR directly supported prevention of mother-to-child transmission programs that allowed nearly 100,000 infants of HIV-infected mothers to be born without HIV, adding to the nearly 340,000 infants born without HIV due to PEPFAR support during 2004-2009. This of course, is not the limit as it is estimated that less than 25% of pregnant HIV-infected women get the care they need (beyond point-of-care transmission prevention). In FY 2010, PEPFAR also directly supported HIV counseling and testing for nearly 33 million people, providing what may be an important entry point to prevention, treatment, and care.

2004 – 2011 PEPFAR Funding ($ in USD millions)
Program

2004

2005

2006

2007

2008

2009

2010

2011

Total

Bilateral HIV/AIDS Programs1

1,643

2,263

2,654

3,699

5,028

5,503

5,542

5,549

26,332

GFATM

547

347

545

724

840

1,000

1,050

1,050

5,053

Bilateral TB Prog’s

87

94

91

95

163

177

243

ND

950

TOTAL PEPFAR (w/o malaria)

2,277

2,705

3,290

4,518

6,031

6,680

6,835

6,599*

32,335

1 Bilateral HIV/AIDS Programs includes funding for bilateral country/regional programs, UNAIDS, IAVI, Microbicides and NIH HIV/AIDS research.
*Possibly not the final total. For final US spending on PEPFAR 2012, please see Fiscal Year 2012 Budget Tracker at http://www.kff.org/globalhealth/8045.cfm.
Note: All funding amounts have been rounded to the nearest million $ so the numbers shown in the table may not sum to the totals.

GFATM

The Global Fund to Fight AIDS, Tuberculosis and Malaria is an international financing institution that invests the world’s money to save lives. To date, it has committed US$ 22.4 billion in 150 countries to support large-scale prevention, treatment and care programs against the three diseases. Round 11 of the grants cycle is now open until 15 Dec 2011. Right now, however, the Fund is unable to provide any accurate forecast or give assurances regarding the level of resources that will actually be available, since very few pledges have been confirmed.

The actual amount available will be influenced by three key considerations: 1) the level and timing of donor pledges, 2) new pledges to be announced at the time of the mid-term replenishment review in March 2012 and 3) the extent of any savings that the Global Fund will achieve through the stringent application of “value for money” and new performance-based funding principles, which can be seen at http://www.theglobalfund.org/en/application/process/eligibility/.

“More donor assistance is urgently needed to close the financing gap in health in the poorest countries of the world… Assistance from developed nations should increase from the current levels of about US$ 6 billion per year globally to US$ 27 billion by 2007 and US$ 38 billion by 2015”, according to the Commission on Macroeconomics and Health, 2003. As can be seen from the chart above, if PEPFAR represents 50% of the Global total, we are far from the target, about 1/3 of where we need to be.

The Global Fund is meant to constitute a major source of this funding. To operate effectively, the Global Fund requires strong and consistent financial commitments from all of its stakeholders. It is thus essential that substantial new pledges are received to finance additional grants and to continue successful programs.

Pledges and contributions from donors are received on an ad-hoc voluntary basis (www.globalfund.org, accessed 24.05.10). The Global Fund is relatively transparent and has an architecture of application, funding structure, management of performance and future planning that is inclusive and as broad-based as a top-down organism from Geneva that disburses money locally can be (www.globalfund.org/en/grantarchitecture). That much being said, the Fund often has to deal with scandals that stop funding from any one or group of countries temporarily. In 2011, we saw this happen with some European countries in what was a fairly small local abuse of funds report (Germany, Sweden and the Netherlands have all re-committed after temporary halts). For other reasons, like the economic downturn that started in 2008 and that shows little sign of abating in many places, Spain and Italy have not contributed the Global Fund for 2011 as of 8 September, which leaves a funding gap of close to half a billion euros. Other European countries with less commitments (Portugal, Ireland, Switzerland) have also not contributed this year.

The World Bank

The World Bank supplies more than just money for drugs – large chunks of its investment is intended for infrastructure of health systems (i.e., child health, health system performance, etc). This money, at least that specifically under AIDS, started to fall in 2004. Although the single year with most money was 2007, it did little to change the overall 3-year rolling average of being half now what it was 6 years ago. The 2010 moneys are at about the 1996 investment level. Which does not mean that infrastructure money may not be coming in under other themes – like malaria, nutrition or tuberculosis (http://search.worldbank.org/projects?qterm=HIV, accessed on 20.05.10). They also lend, offer technical support and analytic work. For example, in light of the current economic crisis, the Bank is supporting countries through technical assistance and collaborative efforts for a joint response by assessing the fiscal implications of scaling up national AIDS programs in Botswana, South Africa, Uganda and Swaziland. They lent some $55 million to African HIV programs in 2010, and expect to lend some $90 million in 2011.

UNAIDS

UNAIDS provides technical support to countries to assist them with expertise and planning for their national AIDS programs, to help ‘make the money work’ for the people on the ground, those that need it most. UNAIDS tracks, evaluates and projects the financial resource requirements at global, regional and country levels to generate reliable and timely information on the epidemic and the response. Based on these evaluations, UNAIDS produces guidelines and progress reports. Much of the international data we juggle is set and approved by UNAIDS. At the 2011 IAS meeting in Rome, they set out a plan of how to move forward in middle- to low-income countries in the face of the current economic downturn. The total investment needs should be met by a combination of sources, each of which has the potential to increase: The first is domestic public investment within low and middle-income countries, which can increase as a result of economic growth in those countries, as well as an increase in the historically relatively low level of priorisation to the AIDS response in their domestic budget. This, while a great idea, is not something that can be “turned on” overnight and while the lobbying for this goes on, people need treatment. A second source is to promote the potential for private financing and philanthropic foundations in low and middle-income countries. A third source would be an increase in the level of donor financing, compatible with a movement in the direction of meeting the target of devoting 0.7% of GDP in OECD countries to development assistance. Needed: Low- to middle-income countries’ domestic health budgets have to average at least 15% of government revenue (as in the Abuja Declaration in Africa). Another promising approach would be to expand innovative mechanisms like indirect taxation (airline tickets, mobile phone usage, exchange rate transactions) to support global health initiatives, and ensure that HIV benefits from these in relation to disease burden. The larger community must continue to support and strengthen existing financial mechanisms, including the Global Fund and relevant UN organizations.

The Bill and Melinda Gates Foundation

The largest private philanthropic organization to date is located in Seattle, US, “focusing on improving people’s health and giving them the chance” to emerge from “hunger and extreme poverty.” They have approximately 957 employees with an endowment of USD 36.3 billion. They have committed USD 25.364 billion since inception and in 2010 committed grants to the tune of USD 2.6 billion in over 100 countries. Much of these moneys are for non-AIDS-specific works, including development (reducing poverty and hunger). In health, they fight and prevent enteric and diarrheal diseases, HIV/AIDS, malaria, pneumonia, TB, neglected and infectious diseases, working on integrated heath solutions, improving delivery of existing tools and supporting research and development in new interventions like vaccines, drugs and diagnostics (http://www.gatesfoundation.org). They have supported the Global Fund with some $650 million as of mid-2010.

Drugs available from whom and where

FDA’s qualification of generics

Generic drugs are important options that allow greater access to health care. Generic drugs approved by FDA have the same high quality, strength, purity and stability as brand-name drugs. And, the generic manufacturing, packaging, and testing sites must pass the same quality standards as those of brand name drugs.

For PEPFAR use, all drugs need FDA approval. As of 2 September 2011, FDA had approved some 132 generic drugs for use in the PEPFAR program that are approved in as short a time as two to six weeks. While quality, strength, purity and stability are guaranteed, administration, delivery and correct use is another issue. For example, a drug approved in May 2010 was a fixed-dose combination of d4T and 3TC. And there the rub. Generics companies (in the case of FDA for PEPFAR, to date there are eleven Indian generics companies, 1 South African company, one company from China and one from the US) copy what is easiest and cheap, not necessarily the most innovative or optimal treatments only. We must continue to try to remind the generics companies that what is best for the patient will continue selling for years, while (hopefully) a less-than-optimal combination like 3TC+d4T has a limited life-time, and can do a lot of harm via side effects along the way.

Lopinavir/r is the first PI approved for generic licensing although there are eight approved PIs on the market in the Global North. Aurobindo got approval for a 25 mg version of ritonavir in early 2009, what could be a very interesting option in boosting in the future. Matrix got an FDA approval of a ritonavir 50 mg version (with lopinavir) on the same day. Matrix and Emcure both have approval for atazanavir (2010).

There are a handful of generics companies with an abacavir approval. As HLA testing for abacavir HSR is not easily available in the Global South, it is very important to train both the medical profession as well as users on diagnosis of HSR and what to do if it occurs, and the importance of never re-starting it once HSR is suspected, things that from an international regulatory agency would be hard to monitor. And although REMS programs from FDA or EMA would accept information on side effects from the Global South (which has up to 5 times the amount of people on drug), they probably contribute little to the overall numbers and thus better definition of safety of these drugs.

In 2011 (until 18 August), FDA has issued one warning letter to one generics company that manufactures HIV products. The letter was unclear about if it was related to an HIV product or not.

In total, in 2011, 400 FDA inspectors will perform more than 2,200 drug-related inspections. FDA takes many different enforcement actions.

WHO-approved generics

Prequalification and quality assurance of antiretroviral products – a fundamental human right

WHO’s Prequalification Programme conducts evaluation and inspection activities and builds national capacity for manufacturing and monitoring high-quality medicines. WHO began reviewing HIV antiretroviral drugs for prequalification in 2001.

In 2005–2006, WHO conducted a quality assurance survey of antiretroviral medicines in Cameroon, the Democratic Republic of the Congo, Kenya, Nigeria, Uganda, United Republic of Tanzania and Zambia. Of the 395 samples tested, none had quality deficiencies that would pose a risk to the people taking them. The results of this and future surveys on drug quality are key to ensuring that the pace of scaling up treatment does not compromise the quality of the medicines available.

Invitations to manufacturers to submit an expression of interest (EOI) for product evaluation are issued not only for HIV/AIDS-related care and treatment products, but also for antimalarial medicines, antituberculosis medicines, influenza-specific antiviral medicines and reproductive health products.

On the WHO List of Prequalified Medicinal Products is an extended list of 290 products (http://apps.who.int/prequal/, accessed 9.09.2011) for HIV/AIDS, made by both originator companies and generics companies. Prequalification may be better described as pre-, on-going, and post-qualification, as they do inspections at all these time points. On this list is atazanavir, which has WHO approval from a BMS manufacturing facility in the US as well as an Indian generics company. Neither Brazil nor Thailand have pre-approved drugs on either list (FDA or WHO) because although they both have and produce generic HIV drugs, they do so only for domestic use.

On the list are many drugs for OIs (acyclovir, ceftriaxone, ciprofloxacin, amongst others). WHO also approves medicines quality control laboratories (QCLs): 21 QCLs are currently prequalified all around the world.

Antiretroviral therapy in low- and middle-income countries by region, December 2009

Region

Estimated number of people receiving ART

Estimated number of people needing ART

ART coverage

Sub-Saharan Africa

3 911 000

10 600 000

37%

Eastern and southern Africa

3 203 000

7 700 000

41%

West and central Africa

709 000

2 900 000

25%

Latin America and the Caribbean

478 000

950 000

50%

Latin America

425 000

840 000

51%

The Caribbean

52 400

110 000

48%

East, South and South-East Asia

739 000

2 400 000

31%

Europe and Central Asia

114 000

610 000

19%

North Africa and the Middle East

12 000

100 000

11%

Total

5 254 000

14 600 000

36%

Source: Towards universal access: scaling up priority HIV/AIDS interventions in the health sector. Progress report 2010 (WHO, UNICEF, UNAIDS), p.53.

With the new threshold of starting treatment at 350 CD4s, even with more people starting treatment, the percentage of those treated who should be on treatment has actually fallen.

A chasm

Improved treatment in line with scientific evidence and recognized international standards of care

Médecins Sans Frontières (MSF, Doctors without Borders) serves approximately 210,000 of the ~5 million people today on treatment, and because they are on the front lines in clinics and health centers in more than 70 countries, their advocacy is not of the ivory tower type. Due to the implementation of ART, they have seen first hand the reduction in mortality for both adults and children, the lowering of incidence of TB as well as the importance of supporting HIV prevention by lowering incidence. They believe that not continuing to invest today in improved treatment and protocols will cost lives down the road, increase a double standard in HIV care and lead to increased costs later. They believe that there is a clear risk that donors may not continue to support or try to delay the implementation of proven and recommended medical strategies for the sake of short-term savings. They recommend:

• Supporting initiation of ART at a CD4 T cell threshold of 350/μl to reduce the incidence of TB and other OIs and improve survival rates, reducing the need for costly and complex acute care.

• Implementing a tenofovir-based first-line regimen will allow patients to stay on their first regimen as long as possible with fewer side effects and delay the need for more costly second-line regimens.

• Providing access to viral load testing to support adherence and detect treatment failure earlier, thereby preventing resistance and needless switching to expensive sub-optimal second-line treatment.

• Supporting innovation that can lead to further improvement and simplification of HIV treatment in resource-poor settings.

According to MSF, most people with HIV/AIDS in need of treatment in the world will die within three years if they do not gain access to treatment now.

How to ensure that prices of drugs and diagnostics remain reasonable?

The international community needs to support policies that will enable funds to stretch as far as possible to meet needs and contain costs in the short- and long-term by ensuring a competitive supply for drugs.

In accordance with the Doha Declaration on TRIPS and Public Health, governments can authorize governmental use or compulsory licenses to ensure generic production of patented products (as in Brazil and Thailand).

Companies and governments can support the Medicines Patent Pool for antiretroviral medicines that originated at UNITAID (www.unitaid.eu), now a freestanding organization at http://www.medicinespatentpool.org. This mechanism brings together patents held by different owners and makes them available to others for generic production and further development. MSF has started a ‘Make It Happen Campaign”. Gilead was the first company to sign on, in July 2011. They are currently negotiating with F. Hoffmann-La Roche, Sequoia Pharmaceuticals, the US National Institutes of Health and ViiV Healthcare. BI and BMS have just started to negotiate. This Pool could save lower income countries more than $1 billion a year in drug costs.

Prices of first-line regimens in low-income countries

The median price paid for tenofovir+3TC+efavirenz (prequalified by WHO) in low-income countries in June 2011 ranged from US$ 143 per person per year for the two pill dose to US$ 173 for the fixed-dose combination. The weighted average median price of the four combinations most widely used in first-line treatment (representing 86% of the prescribed first-line treatments in low-income countries) was US$ 170 per person per year in 2007. The decline in drug prices between 2004 and 2007 can be attributed to the scaling up of treatment programs, increased competition between a growing number of products prequalified by WHO, new pricing policies by pharmaceutical companies and successful negotiations between the William J. Clinton Foundation (CHAI) and major generic manufacturers. While combinations with d4T are cheaper, and studies continue to be carried out with even-lower doses, etc, the long-term side effects do not outweigh the harm, and programs should move to tenofovir-containing regimens as soon as they can.

Second-line regimens

Second-line regimens are still significantly more expensive than first-line regimens in low- and middle-income countries. In 2011, the median cost of a regimen of AZT/3TC+atazanavir/r, a newly indicated second-line regimen, was US$ 442 in low-income countries and up to six times that in middle-income countries. The actual prices paid for second-line regimens vary significantly between countries. For example, South Africa pays an average price of US$ 1,600 per person per year for ddI+abacavir+lopinavir/r, whereas El Salvador paid US$ 3,448 per person per year for the same regimen in 2007.

In the UK, a recent study showed that first-line treatments can last 8 years or longer, but by then, of those who start, more than 25% of people will have failed (UK Chic 2010). If ARV access started in earnest in 2002, we are at the 8-year mark. What to do with the approximately 1 million people who must need to move to a new regimen? And of the regimens that fail, NNRTIs fail at a rate almost three times higher than the rate of PIs. Most people in resource-limited settings are on an NNRTI containing regimen. MSF estimates that regimen failure is “largely under-diagnosed” due to limited lab facilities for viral load testing, which can only lead to resistance and harder-to-construct post-first-line regimens.

How to expand treatment to more people plus switch those currently failing to an effective regimen, all within a framework of cutting back on donor spending?

As the absolute numbers of people who need access to second-line regimens continue to grow, addressing the high cost of second-line regimens will become increasingly important to ensure the most cost-effective use of available resources. A third-line treatment is currently US$ 2766 in low-income, US$ 5870 in middle-income countries.

Future Funding

As funding stalls, major funders – US, UK, Netherlands, France, Germany, Norway and Sweden – may be becoming fatigued. In 2001 at the UNGCP meeting, recipient countries were asked to dedicate 15% of their national budgets to health, agreed to n theory by the Abuja Declaration. Only 8 countries have done so. More than half of African countries spend less than the UN minimum of 34 US$ per capita.

New strategies have to be developed – small taxes on currency transactions, etc. Small airline ticket tax from many countries (see above). Product (Red) is a fund-raiser of the Global Fund that coordinates profits from sales from partner businesses and has recently reached the USD 170 million mark.

As mainstays of program centers are at best maintaining previous amounts (flat-funding, like PEPFAR) or unclear about their budgets for this year (GFATM), it is important that we all contribute, both economically and using advocacy, about how to continue to arrive to the amount needed (USD 25.1 billion/yr).

Europe gets involved

The European Union can impact access to medicines for developing countries through its policies, legislation and bilateral and regional trade agreements. The EU can adopt appropriate measures to improve access to existing medical tools (medicines, diagnostics, vaccines) as well as stimulate the research and development of better tools for people in resource-starved countries. The Working Group on Innovation, Access to Medicines and Poverty-Related Diseases will create a meaningful dialogue between Members of the European Parliament, the European Commission, and civil society.

More problems than solutions

It is quite possibly easier to flag the difficulties than offer or implement solutions, but one survey was recently carried out, this time by Oxfam. In a recent analysis of meeting the Millenium Development Goals, they criticized Europe overall as not valuing poor people “enough to … guarantee … by making aid commitments legally binding. … This year alone, the EU is 19 billion euros short of its targets … enough to have saved 3 million lives in poor countries.” They have started a Robin Hood tax (a tiny tax on bankers that could generate billions of US$). In their change.org blog, they say that donors are not transparent with how their money is spent and where. For example, they highlight Kenya, where PEPFAR purportedly spent over one 500 million dollars on AIDS programs in 2008. A representative of the Kenyan Ministry of Health says that they cannot get “a list of partners, where they are working, how much they are spending, on what” from the US (http://globalpoverty.change.org/blog/view/how_transparent_is_us_foreign_aid). Which makes an integrated strategy on AIDS hard to accomplish. Without being too blithe, imagine that happening in the North: we knew how much we are spending, but not on what!

The unconscionable health gap: a global plan for justice

In the Lancet, Lawrence Gostin outlined a plan for health access for all (Gostin 2010). Despite robust international norms, health disparities render a person’s likelihood of survival drastically different depending on where she or he is born. WHO urges “closing the health gap in a generation” through action on the social determinants of health.

International health assistance has quadrupled over two decades rising to US$21.8 billion in 2007 (Ravishankar 2009). This level of funding might seem impressive but sits modestly beside the annual $1.5 trillion spent globally on military expenditures (2.43% of global gross domestic product), and $300 billion in agricultural subsidies.

Foreign aid simply is not predictable and scalable to needs and often reflects donors’ geostrategic interests rather than the key determinants of health. Developed countries recognize the health gap, but are resistant to taking bold remedial action.

If the health gap is unfair and unacceptable, how can the international community be galvanized to make a genuine difference? A global plan for justice would be a voluntary compact between states and their partners. It would simply encourage WHO to exercise its constitutional powers and leadership.

A global plan for justice would set achievable funding targets for a global health fund to be distributed according to need (Ooms 2008). Although WHO would negotiate the funding levels, developed countries could donate, for example, 0.25% of gross national income (GNI) per annum, in addition to current foreign assistance.

A global plan for justice would guarantee a universal package of essential services, comprising three core components: essential vaccines and medicines, basic survival needs, and adaption to climate change.

The international community must do more than lament ongoing, unconscionable health inequalities. It must act boldly and with a shared voice, such as through a global plan for justice. If the world does not act, the avoidable suffering and early death among the world’s least healthy people will continue unabated—a breach of social justice that is no longer ethically acceptable (Gostin 2010).

The amount of people who need access to ART in the next few years – in the short term – will grow substantially. Because of this, we need to keep up the pressure on all actors – donor organisations as well as individual nations, manufacturers, health care workers and affected communities of all sizes – to do their part in order to provide the most current and useful treatment strategies possible, to whole populations. In order to achieve this, we can not sit idly by and hope for the best – we must continue to push that boulder up the hill for as long as it takes so everyone who needs it has access to treatment and care as early and for as long as necessary.

 

Because global access is such a moving target, all references are web-based and in the text.

References

Collaborative Group on HIV Drug Resistance and UK CHIC Study Group. Long-term probability of detecting drug-resistant HIV in treatment-naïve patients initiating combination antiretroviral therapy. Clin Infect Dis 2010, 50: 1275-85.

Gostin L. The unconscionable health gap: a global plan for justice. Lancet 2010, 375:1504-5.

Harrigan RP. HIV drug resistance over the long haul. Clin Infect Dis 2010, 50: 1286-87.

Ooms G, Hammonds R. Correcting globalization in health: transnational entitlements versus the ethical imperative of reducing aid-dependency. Public Health Ethics 2008; 1: 154-170.

Ravishankar N, Gubbins P, Cooley RJ, et al. Financing of global health: tracking development assistance for health from 1990 to 2007. Lancet 2009; 373: 2113-2124.

Greener R. Financing the response to HIV in low- and middle-income countries: how it is affected by the economic crisis? UNAIDS presentation at IAS Rome, 20 July 2011.

Utw.msfaccess.org, Untangling the web of antiretroviral price reductions, 14th edition, Medecins Sans Frontieres, July 2011.

Links

Europe is Missing in Action, http://www.oxfam.org/en/pressroom/pressrelease/2010-06-17/europe-missing-action-when-should-be-leading-poverty-charge, 17 June 2010

FDA enforcement actions in the year 2008, http://www.fda.gov/downloads/ICECI/EnforcementActions/EnforcementStory/UCM129812.pdf.

http://www.globalfund.org/en/applicantsimplementers/resources/?lang=en

PEPFAR, http://www.pepfar.gov/press/80064.htm

 “Punishing Success? Early Signs of a Retreat from Commitment to HIV/AIDS Care and Treatment”, November 2009, http://www.msf.org/msfinternational/ accessed online 29.04.10.

http://www.msfaccess.org/main/access-patents/european-parliament-working-group/about-working-group/

World Health Assembly. Reducing health inequities through action on the social determinants of health, http://apps.who.int/gb/ebwha/pdf_files/EB124/B124_R6-en.pdf, accessed Jan 4, 2010

UNAIDS, http://www.unaids.org/en/resources/presscentre/pressreleaseandstatementarchive/2011/june/20110610psdeclaration/

http://www.un.org/en/ga/aidsmeeting2011/

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Filed under 6.13. Global Access to HIV Treatment, 6.9. Salvage Therapy, Part 2 - Antiretroviral Therapy